Hereditary alpha tryptasemia (HαT) is found in approximately 7% of the population. Associations with a variety of clinical symptoms including gastric reflux, joint hypermobility, dysautonomia, ...flushing and pruritus, and hymenoptera allergy have variably been described in prior reports. However, our understanding of this genetic trait is limited by a paucity of published studies, referral bias, and conflicting findings at clinical presentation.
The purpose of this study was to assess the clinical phenotype of HαT in a random biorepository population and in patients with and without mastocytosis referred to the allergy clinic.
Tryptase copy number allele was assessed using digital droplet PCR. Participants with or without HαT were interviewed and examined by a clinician and surveyed regarding their medical history and symptomology.
HαT was identified in 7.5% of the random biorepository samples and in 18% of patients with mastocytosis. There was no difference in the clinical symptomology or medical history of individuals with HαT compared to controls. Average baseline serum tryptase was higher in individuals with HαT compared to controls, but there was no difference in urinary mast cell activation products.
Elevated baseline serum tryptase was the only consistent phenotypic marker for HαT in this study. There was a higher frequency of HαT in patients with mastocytosis than in the general population.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Much of Covid-19 hyperinflammation is consistent with mast-cell-driven inflammation.•Prevalence of severe Covid-19 is similar to that of mast cell activation syndrome (MCAS).•Drugs inhibiting mast ...cells (MCs) and their mediators show promise in Covid-19.•None of the authors currently treated MCAS patients with Covid-19 had severe forms or mortality.•The dysfunctional MCs of MCAS may underlie severe acute and chronic Covid-19 illness.
One-fifth of Covid-19 patients suffer a severe course of Covid-19 infection; however, the specific causes remain unclear. Mast cells (MCs) are activated by SARS-CoV-2. Although only recently recognized, MC activation syndrome (MCAS), usually due to acquired MC clonality, is a chronic multisystem disorder with inflammatory and allergic themes, and an estimated prevalence of 17%. This paper describes a novel conjecture explaining how MCAS might cause a propensity for severe acute Covid-19 infection and chronic post-Covid-19 illnesses.
Observations of Covid-19 illness in patients with/without MCAS were compared with extensive clinical experience with MCAS.
The prevalence of MCAS is similar to that of severe cases within the Covid-19-infected population. Much of Covid-19’s hyperinflammation is concordant with manners of inflammation which MC activation can drive. Drugs with activity against MCs or their mediators have preliminarily been observed to be helpful in Covid-19 patients. None of the authors’ treated MCAS patients with Covid-19 suffered severe infection, let alone mortality.
Hyperinflammatory cytokine storms in many severely symptomatic Covid-19 patients may be rooted in an atypical response to SARS-CoV-2 by the dysfunctional MCs of MCAS rather than a normal response by normal MCs. If proven, this theory has significant therapeutic and prognostic implications.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mast cell activation syndrome (MCAS) is a term applied to several clinical entities which have gained increased attention from patients and medical providers. While several descriptive publications ...about MCAS exist, there are many gaps in knowledge resulting in confusion about this clinical syndrome. Whether MCAS is a primary syndrome or exists as a constellation of symptoms in the context of known inflammatory, allergic, or clonal disorders associated with systemic mast cell (MC) activation is not well understood. More importantly, the underlying mechanisms and pathways that lead to MC activation in MCAS patients remain to be elucidated.
The purpose of this manuscript is to summarize the known literature, identify gaps in knowledge, and highlight research needs. Several topics are covered: 1) Contextualization of MCAS and MCAS-like endotypes and related diagnostic evaluations; 2) Mechanistic research; 3) Management of typical and refractory symptoms, and 4) MCAS-specific education for patients and healthcare providers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Mast cell activation symptoms (MCAS) were increased in Long-COVID patients•Long-COVID patients had similar severity of numerous MCAS symptoms•Aberrant mast cells induced by SARS-CoV-2 infection is ...the likely triggering factor•MC-directed therapy could help treat Long-COVID patients
Hyper-inflammation caused by COVID-19 may be mediated by mast cell activation (MCA) which has also been hypothesized to cause Long-COVID (LC) symptoms. We determined prevalence/severity of MCA symptoms in LC.
Adults in LC-focused Facebook support groups were recruited for online assessment of symptoms before and after COVID-19. Questions included presence and severity of known MCA and LC symptoms and validated assessments of fatigue and quality of life. General population controls and mast cell activation syndrome (MCAS) patients were recruited for comparison if they were ≥18 years of age and never had overt COVID-19 symptoms.
There were 136 LC subjects (89.7% females, age 46.9 ±12.9 years), 136 controls (65.4% females, age 49.2 ±15.5), and 80 MCAS patients (85.0% females, age 47.7 ±16.4). Pre-COVID-19 LC subjects and controls had virtually identical MCA symptom and severity analysis. Post-COVID-19 LC subjects and MCAS patients prior to treatment had virtually identical MCA symptom and severity analysis.
MCA symptoms were increased in LC and mimicked the symptoms and severity reported by patients who have MCAS. Increased activation of aberrant mast cells induced by SARS-CoV-2 infection by various mechanisms may underlie part of the pathophysiology of LC, possibly suggesting routes to effective therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mast cell activation disease
(MCAD) is a term referring to a heterogeneous group of disorders characterized by aberrant release of variable subsets of mast cell (MC) mediators together with ...accumulation of either morphologically altered and immunohistochemically identifiable mutated MCs due to MC proliferation (systemic mastocytosis SM and MC leukemia MCL) or morphologically ordinary MCs due to decreased apoptosis (MC activation syndrome MCAS and well-differentiated SM). Clinical signs and symptoms in MCAD vary depending on disease subtype and result from excessive mediator release by MCs and, in aggressive forms, from organ failure related to MC infiltration. In most cases, treatment of MCAD is directed primarily at controlling the symptoms associated with MC mediator release. In advanced forms, such as aggressive SM and MCL, agents targeting MC proliferation such as kinase inhibitors may be provided. Targeted therapies aimed at blocking mutant protein variants and/or downstream signaling pathways are currently being developed. Other targets, such as specific surface antigens expressed on neoplastic MCs, might be considered for the development of future therapies. Since clinicians are often underprepared to evaluate, diagnose, and effectively treat this clinically heterogeneous disease, we seek to familiarize clinicians with MCAD and review current and future treatment approaches.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
An elevated basal serum tryptase level is associated with severe systemic anaphylaxis, most notably caused by Hymenoptera envenomation. Although clonal mast cell disease is the culprit in some ...individuals, it does not fully explain this clinical association.
Our aim was to determine the prevalence and associated impact of tryptase genotypes on anaphylaxis in humans.
Cohorts with systemic mastocytosis (SM) and venom as well as idiopathic anaphylaxis from referral centers in Italy, Slovenia, and the United States, underwent tryptase genotyping by droplet digital PCR. Associated anaphylaxis severity (Mueller scale) was subsequently examined. Healthy volunteers and controls with nonatopic disease were recruited and tryptase was genotyped by droplet digital PCR and in silico analysis of genome sequence, respectively. The effects of pooled and recombinant human tryptases, protease activated receptor 2 agonist and antagonist peptides, and a tryptase-neutralizing mAb on human umbilical vein endothelial cell permeability were assayed using a Transwell system.
Hereditary α-tryptasemia (HαT)—a genetic trait caused by increased α-tryptase–encoding Tryptase-α/β1 (TPSAB1) copy number resulting in elevated BST level—was common in healthy individuals (5.6% n = 7 of 125) and controls with nonatopic disease (5.3% n = 21 of 398). HαT was associated with grade IV venom anaphylaxis (relative risk = 2.0; P < .05) and more prevalent in both idiopathic anaphylaxis (n = 8 of 47; 17%; P = .006) and SM (n = 10 of 82 12.2%; P = .03) relative to the controls. Among patients with SM, concomitant HαT was associated with increased risk for systemic anaphylaxis (relative risk = 9.5; P = .007). In vitro, protease-activated receptor-2–dependent vascular permeability was induced by pooled mature tryptases but not α- or β-tryptase homotetramers.
Risk for severe anaphylaxis in humans is associated with inherited differences in α-tryptase–encoding copies at TPSAB1.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose of Review
The current article aims to provide a comprehensive update on diagnostic criteria for mast cell activation syndrome (MCAS), addressing challenges in diagnosing and classifying MCAS ...and its variants.
Recent Findings
In recent years, there has been a significant increase in our knowledge regarding the underlying mechanisms responsible for the activation of mast cells (MCs) in various pathological conditions. Furthermore, a set of criteria and a classification for MCASs have been established. MCAS is characterized by the presence of typical clinical symptoms, a substantial elevation in serum tryptase levels during an attack compared to the patient’s baseline tryptase levels, and a response to MC mediator–targeting therapy.
Summary
In this report, a thorough examination was conducted on the contemporary literature relating to MCAS, with a focus on comparing the specificity, sensitivity, and robustness of MCAS-related parameters within proposals for diagnosing and classifying MCAS and its variants. Moreover, the significance of employing specific consensus criteria in the assessment and categorization of MCAS in individual patients was underscored, due to the escalating occurrence of patients receiving a misdiagnosis of MCAS based on nonspecific criteria.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose of Review
Provide an overview of the expanding landscape of mast cell (MC)–targeting treatments in mast cell activation syndromes (MCAS).
Recent Findings
Tyrosine-kinase inhibitors (TKIs) ...targeting wild-type and mutated KIT can efficiently induce MC depletion. Avapritinib and midostaurin can also temper IgE-mediated degranulation. Avapritinib has been recently approved by the FDA for the treatment of indolent systemic mastocytosis (ISM). Targeting activation pathways and inhibitory receptors is a promising therapeutic frontier. Recently, the anti Siglec-8 antibody lirentelimab showed promising results in ISM.
Summary
MCAS is a heterogeneous disorder demanding a personalized therapeutic approach and, especially when presenting as anaphylaxis, has not been formally captured as outcome in prospective clinical trials with TKI. Long-term safety of TKI needs to be addressed. New drugs under investigation in diseases in which non-neoplastic MCs play a pivotal role can provide important inputs to identify new efficient and safe treatments for MCAS.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Gastrointestinal (GI) symptoms are commonly reported in patients with mast cell disease. GI involvement in systemic mastocytosis is heterogeneous and symptoms may be caused by infiltration of ...abnormal mast cells in the GI tract and/or by the downstream effect of mast cell mediators on GI tissues. GI symptoms described the monoclonal mast cell activation syndrome are best characterized in the context of acute anaphylaxis. The presence of GI symptoms and a subjective response of symptoms to anti-mast cell mediator therapy are considered qualifying criteria in the diagnosis of the idiopathic mast cell activation syndrome. Antimediator therapy may help alleviate GI symptoms in mast cell disease.
Background
Current diagnostic algorithms for systemic mastocytosis (SM) rely on the detection of KITD816V in blood to trigger subsequent bone marrow (BM) investigations.
Methods
Here, we correlated ...the KITD816V mutational status of paired blood and BM samples from 368 adults diagnosed with mast cell activation syndrome (MCAS) and mastocytosis and determined the potential utility of investigating KITD816V in genomic DNA from blood‐purified myeloid cell populations to increase diagnostic sensitivity. In a subset of 69 patients, we further evaluated the kinetics of the KITD816V cell burden during follow‐up and its association with disease outcome.
Results
Our results showed a high correlation (P < .0001) between the KITD816V mutation burden in blood and BM (74% concordant samples), but with a lower mean of KITD816V‐mutated cells in blood (P = .0004) and a high rate of discordant BM+/blood− samples particularly among clonal MCAS (73%) and BM mastocytosis (51%), but also in cutaneous mastocytosis (9%), indolent SM (15%), and well‐differentiated variants of indolent SM (7%). Purification of different compartments of blood‐derived myeloid cells was done in 28 patients who were BM mast cell (MC)+/blood− for KITD816V, revealing KITD816V‐mutated eosinophils (56%), basophils (25%), neutrophils (29%), and/or monocytes (31%) in most (61%) patients. Prognostically, the presence of ≥3.5% KITD816V‐mutated cells (P < .0001) and an unstable KITD816V mutation cell burden (P < .0001) in blood and/or BM were both associated with a significantly shortened progression‐free survival (PFS).
Conclusions
These results confirm the high specificity but limited sensitivity of KITD816V analysis in whole blood for the diagnostic screening of SM and other primary MCAS, which might be overcome by assessing the mutation in blood‐purified myeloid cell populations.
This study evaluates the utility of KITD816V mutational status in blood (vs. bone marrow) for the diagnostic screening of SM and MCAS patients, having a high specificity but a limited sensitivity in patients presenting with clonal MCAS without skin lesions. Assessment of KITD816V in blood‐purified myeloid cell populations increases the diagnostic sensitivity of this mutation in 61% of patients. Further, an unstable (decrease or increase) KIT mutation cell burden during follow‐up is a strong predictor of shortened progression‐free survival in SM.Abbreviations: BM, bone marrow; KITD816V, somatic mutation in codon 816 of the stem cell growth factor receptor gene; MC, mast cell; MCAS, mast cell activation syndromes; No., number; PFS, progression‐free survival; SM, systemic mastocytosis
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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