Publications by authors named "Cem Akin"

126 Publications

Idiopathic Anaphylaxis: a Perplexing Diagnostic Challenge for Allergists.

Authors:
Theo Gulen Cem Akin

Curr Allergy Asthma Rep 2021 Feb 9;21(2):11. Epub 2021 Feb 9.

Division of Allergy and Clinical Immunology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA.

Purpose Of Review: The aim of this systematic review is to present the proposed theories of pathogenesis for idiopathic anaphylaxis (IA), to discuss its classification, its diagnostic approach, and management.

Recent Findings: IA represents a major diagnostic challenge and is diagnosed when excluding the possible identifiable triggers of anaphylaxis. The current research, however, revealed that certain conditions including mastocytosis, mast cell activation syndromes, and hereditary alpha tryptasemia can masquerade and overlap with its symptomatology. Also, newly identified galactose-alpha-1,3-galactose mammalian red meat allergy has recently been recognized as underlying cause of anaphylaxis in some cases that were previously considered as IA. IA comprises a heterogenous group of conditions where, in some cases, inherently dysfunctional mast cells play a role in pathogenesis. The standard trigger avoidance strategies are ineffective, and episodes are unpredictable. Therefore, prompt recognition and treatment as well as prophylaxis are critical. The patients should always carry an epinephrine autoinjector.
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http://dx.doi.org/10.1007/s11882-021-00988-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873102PMC
February 2021

A Challenge for Allergologist: Application of Allergy Diagnostic Methods in Mast Cell Disorders.

Int J Mol Sci 2021 Feb 1;22(3). Epub 2021 Feb 1.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria.

Primary and secondary mast cell activation syndromes (MCAS) can occur in patients with mastocytosis. During the past few years our knowledge about the pathogenesis and disease-triggering mechanisms in MCAS and mastocytosis have increased substantially. Whereas mastocytosis is characterized by an accumulation of neoplastic (clonal) mast cells (MC) in various organ systems, MCAS is defined by a massive and systemic activation of these cells. Mast cells are crucial effector cells in allergic diseases, thus their elevated number and activation can cause severe anaphylactic reactions and MCAS in patients with mastocytosis. However, these cells may also degranulate spontaneously or degranulate in response to non-allergic triggers leading to clinical symptoms. In mastocytosis patients, such symptoms may lead to the diagnosis of a primary MCAS. The diagnosis of a concomitant allergy in mastocytosis patients is challenging. In these patients, a mixed form (primary and secondary) of MCAS may be diagnosed. These patients may also suffer from life-threatening anaphylactic reactions when exposed to allergens. In these cases, the possibility of severe side effects of in vivo provocations can sometimes also limit diagnostic evaluations. In the current article, we discuss the diagnosis and management of patients suffering from mastocytosis and concomitant MCAS, with special emphasis on novel diagnostic tests and management, including allergen microarrays, recombinant allergen analysis, basophil activation tests, optimal prophylaxis, and specific therapies.
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http://dx.doi.org/10.3390/ijms22031454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867197PMC
February 2021

Diagnosis, Classification and Management of Mast Cell Activation Syndromes (MCAS) in the Era of Personalized Medicine.

Int J Mol Sci 2020 Nov 27;21(23). Epub 2020 Nov 27.

Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD 20852, USA.

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 -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 -mutated MCs are identified. Most severe MCA events occur in combined forms of MCAS, where -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.
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http://dx.doi.org/10.3390/ijms21239030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731385PMC
November 2020

Patients with mast cell activation symptoms and elevated baseline serum tryptase level have unique bone marrow morphology.

J Allergy Clin Immunol 2020 Nov 25. Epub 2020 Nov 25.

Harvard Medical School, Boston, Mass; Department of Pathology, Brigham and Women's Hospital, Boston, Mass.

Background: Patients with mast cell (MC) activation symptoms and elevated baseline serum tryptase level (MCAS-T) may not necessarily have a clonal MC disorder. Many are diagnosed with hereditary α-tryptasemia (HαT), a genetic trait characterized by autosomal dominant inheritance of multiple copies of TPSAB1 encoding α-tryptase and increased risk for severe anaphylaxis.

Objective: The aim of our study was to identify and characterize bone marrow MC histopathologic features specific for MCAS-T.

Methods: A total of 43 patients with MCAS-T underwent evaluation, including bone marrow biopsy, for a MC disorder. The results of the work-up for clonal MC disorders such as systemic mastocytosis and monoclonal MC activation syndrome were negative. Bone marrow MC histopathology was reviewed to identify characteristic features of MCAS-T. A subgroup of patients was available for tryptase genotyping.

Results: Patients with MCAS-T showed unique morphologic and histologic features when compared with controls. MCs were larger (P < .01), hypogranular (P < .01), frequently detected in paratrabecular (P < .05) and perivascular (P < .01) locations, and associated with bone marrow eosinophilia (P < .01). A total of 10 patients who were available for tryptase genotyping were all confirmed to have HαT. This subgroup was representative of the larger MCAS-T cohort.

Conclusion: We report unique bone marrow MC phenotypic and histopathologic changes in patients with MCAS-T. These morphologic changes are associated with an elevated tryptase level that has been confirmed to be caused by HαT in all patients available for testing.
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http://dx.doi.org/10.1016/j.jaci.2020.11.017DOI Listing
November 2020

Practical management of adverse events in patients with advanced systemic mastocytosis receiving midostaurin.

Expert Opin Biol Ther 2021 Jan 15:1-12. Epub 2021 Jan 15.

University Hospital Mannheim, Heidelberg University , Mannheim, Germany.

Introduction: Systemic mastocytosis (SM) is characterized by the overproduction and accumulation of neoplastic mast cells (MCs) in the bone marrow, skin, and visceral organs. The D816V mutation is found in approximately 90% of cases. In advanced SM (advSM), inferior survival often relates to MC-induced organ damage that may impact multiple organ systems. In addition, mediator symptoms related to MC activation can severely impact the quality of life. The oral multikinase/KIT inhibitor midostaurin was approved by the US Food and Drug Administration and the European Medicines Agency as monotherapy for advSM based on data from phase 2 clinical studies.

Areas Covered: This review discusses the management of common adverse events (AEs) in patients with advSM who participated in phase 2 clinical studies that led to the approval of midostaurin.

Expert Opinion: In the advSM population undergoing treatment with midostaurin, treatment-related AEs are often difficult to distinguish from disease-related symptoms, which can lead to premature discontinuation and improper dose reduction of midostaurin therapy in patients who might have benefitted from continued therapy. Here we present strategies to help optimize AE management and maximize the potential benefits of midostaurin in advSM.
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http://dx.doi.org/10.1080/14712598.2021.1837109DOI Listing
January 2021

Accurate Diagnosis and Prognosis in Systemic Mastocytosis: The Role of Mutational Analysis.

J Allergy Clin Immunol Pract 2020 Oct;8(9):3128-3129

Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, Mich.

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http://dx.doi.org/10.1016/j.jaip.2020.06.030DOI Listing
October 2020

Mast cells as a unique hematopoietic lineage and cell system: From Paul Ehrlich's visions to precision medicine concepts.

Theranostics 2020 29;10(23):10743-10768. Epub 2020 Aug 29.

Departments of Pathology and of Microbiology and Immunology, and the Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, USA.

The origin and functions of mast cells (MCs) have been debated since their description by Paul Ehrlich in 1879. MCs have long been considered 'reactive bystanders' and 'amplifiers' in inflammatory processes, allergic reactions, and host responses to infectious diseases. However, knowledge about the origin, phenotypes and functions of MCs has increased substantially over the past 50 years. MCs are now known to be derived from multipotent hematopoietic progenitors, which, through a process of differentiation and maturation, form a unique hematopoietic lineage residing in multiple organs. In particular, MCs are distinguishable from basophils and other hematopoietic cells by their unique phenotype, origin(s), and spectrum of functions, both in innate and adaptive immune responses and in other settings. The concept of a unique MC lineage is further supported by the development of a distinct group of neoplasms, collectively referred to as mastocytosis, in which MC precursors expand as clonal cells. The clinical consequences of the expansion and/or activation of MCs are best established in mastocytosis and in allergic inflammation. However, MCs have also been implicated as important participants in a number of additional pathologic conditions and physiological processes. In this article, we review concepts regarding MC development, factors controlling MC expansion and activation, and some of the fundamental roles MCs may play in both health and disease. We also discuss new concepts for suppressing MC expansion and/or activation using molecularly-targeted drugs.
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http://dx.doi.org/10.7150/thno.46719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482799PMC
August 2020

Risk and management of patients with mastocytosis and MCAS in the SARS-CoV-2 (COVID-19) pandemic: Expert opinions.

J Allergy Clin Immunol 2020 08 17;146(2):300-306. Epub 2020 Jun 17.

Division of Allergy, Department of Dermatology, and Department of Biomedicine, University of Basel, Basel, Switzerland.

The coronavirus disease 2019 (COVID-19) (caused by severe acute respiratory syndrome coronavirus 2) pandemic has massively distorted our health care systems and caused catastrophic consequences in our affected communities. The number of victims continues to increase, and patients at risk can only be protected to a degree, because the virulent state may be asymptomatic. Risk factors concerning COVID-19-induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. Because no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Although the overall risk to acquire the severe acute respiratory syndrome coronavirus 2 may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain comorbidities, mast cell activation-related events affecting the cardiovascular or bronchopulmonary system, and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. In contrast, other therapies, such as anti-mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider.
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http://dx.doi.org/10.1016/j.jaci.2020.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297685PMC
August 2020

Midostaurin improves quality of life and mediator-related symptoms in advanced systemic mastocytosis.

J Allergy Clin Immunol 2020 08 11;146(2):356-366.e4. Epub 2020 May 11.

University Medical Center Groningen, Department of Hematology, University of Groningen, Groningen, The Netherlands.

Background: Advanced systemic mastocytosis (advSM) is characterized by presence of the KIT D816V mutation and pathologic accumulation of neoplastic mast cells (MCs) in various tissues, leading to severe symptoms and organ damage (eg, cytopenias, liver dysfunction, portal hypertension, malabsorption, and weight loss). Treatment with midostaurin, an orally active multikinase/KIT inhibitor now approved for advSM in the United States and the European Union, resulted in a high rate of response accompanied by reduced MC infiltration of the bone marrow and lowered serum tryptase level.

Objective: We aimed to determine whether midostaurin improves health-related quality of life (QOL) and MC mediator-related symptoms in patients with advSM.

Methods: In 116 patients with systemic mastocytosis (89 patients with advSM fulfilling the strict inclusion criteria of the D2201 study [ClinicalTrials.gov identifier NCT00782067]), QOL and symptom burden were assessed during treatment with midostaurin by using the 12-Item Short-Form Health Survey (SF-12) and the Memorial Symptom Assessment Scale patient-reported questionnaires, respectively. MC mediator-related symptoms were evaluated by using a specific physician-reported questionnaire.

Results: Over the first 6 cycles of treatment with midostaurin (ie, 6 months), patients experienced significant improvements in total SF-12 and Memorial Symptom Assessment Scale scores, as well as in subscores of each instrument. These improvements were durable during 36 months of follow-up. Similarly, we found substantial improvements (67%-100%) in all MC mediator-related symptoms.

Conclusion: QOL and MC mediator-related symptoms significantly improve with midostaurin treatment in patients with advSM (ClinicalTrials.gov identifier, NCT00782067).
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http://dx.doi.org/10.1016/j.jaci.2020.03.044DOI Listing
August 2020

Non-hematologic diagnosis of systemic mastocytosis: Collaboration of radiology and pathology.

Blood Rev 2021 Jan 8;45:100693. Epub 2020 Apr 8.

Division of Hematology, Oncology and Cellular Therapy, Department of Medicine, Rush University, Chicago, IL, USA. Electronic address:

Systemic mastocytosis (SM) is a hematologic disease with a wide range of clinical courses ranging from an indolent condition with normal life expectancy to exceedingly aggressive disorder with a poor prognosis. The symptoms and signs of SM result from the release of mast cell mediators with heterogeneous functions, and/or organ damage from neoplastic mast cell infiltration, or both. Diagnostic criteria for SM are well-defined by the World Health Organization (WHO). However, the diagnosis of SM can be difficult when especially it is not in the differential diagnosis. Routinely used radiologic techniques (e.g., X-ray, ultrasound, CT scans can show findings such as lytic-, sclerotic- or mixed-bone lesions, splenomegaly, hepatomegaly, retroperitoneal or periportal mesenteric lymphadenopathy, and omental thickening). It is essential to emphasize that the constellation of these radiologic findings should strongly concern of SM, especially in patients who also have a skin rash, allergic reactions, gastrointestinal tract symptoms (lasting, intermittent nausea, diarrhea), paroxysmal tachycardias, unexplained weight loss, persistent bone pain, cytopenias, liver dysfunction, eosinophilia. These findings, even coincidentally noted, will likely lead to a tissue biopsy, which reveals diagnosis (as we discussed and illustrated some tissue biopsies here). Moreover, the role of MRI and new techniques such as [18-fluorodeoxyglucose positron emission computed tomography, fibroscan] in the diagnosis of SM have been discussed. Furthermore, we reviewed the use of radiologic methods to evaluate treatment response and prognostication of SM..
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http://dx.doi.org/10.1016/j.blre.2020.100693DOI Listing
January 2021

Idiopathic Anaphylaxis: A Form of Mast Cell Activation Syndrome.

J Allergy Clin Immunol Pract 2020 04;8(4):1196-1201

Brigham and Women's Hospital, Division of Allergy and Clinical Immunology, Boston, Mass; Harvard Medical School, Boston, Mass.

Idiopathic anaphylaxis is a condition caused by paroxysmal episodes of sudden-onset multiorgan involvement variably including laryngeal edema, urticaria, bronchoconstriction, dyspnea, hypoxia, abdominal pain, nausea, vomiting, diarrhea, and hypotension. Rarely, the episodes can lead to cardiovascular collapse and death in the absence of a clear trigger, especially in the presence of other cardiovascular comorbidities. Elevated mast cell mediators such as tryptase and histamine have been reported during episodes, and mast cells are considered the primary cells responsible for driving anaphylaxis in humans. Basophils also secrete histamine and LTC4 when activated and theoretically can contribute to symptoms. As our understanding of mast cell disorders continue to grow, the classification for these disorders evolves. The purpose of this article was 2-fold: to review the epidemiology, clinical manifestations, and diagnosis of idiopathic anaphylaxis and to discuss the classification of idiopathic anaphylaxis within the broader context of mast cell activation disorders.
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http://dx.doi.org/10.1016/j.jaip.2019.10.048DOI Listing
April 2020

New developments in the field of mastocytosis and mast cell activation syndromes: a summary of the Annual Meeting of the European Competence Network on Mastocytosis (ECNM) 2019.

Leuk Lymphoma 2020 05 26;61(5):1075-1083. Epub 2019 Dec 26.

Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria.

Mastocytosis are a group of hematologic neoplasms characterized by an accumulation of atypical mast cells in one or several organs/tissues, often accompanied by mast cell activation. Whereas in children the disease manifestations are mostly limited to the skin, in adults the disease is usually systemic (systemic mastocytosis; SM) and involves the bone marrow and/or other internal organs. Several variants of SM have been defined. Whereas most patients have indolent SM, some patients have advanced SM, which underlines the complexity of SM. In 2002, a European consortium of clinicians and scientists initiated a multidisciplinary, multi-national cooperative network, termed the 'European Competence Network on Mastocytosis' (ECNM), with the aim to improve diagnosis and therapy of patients with mastocytosis and other mast cell activation disorders. Since then, members of the ECNM have organized Annual Meetings in several European countries. The present article provides a summary of advances in the field presented during the 17th Annual ECNM meeting held in Salzburg in October 2019.
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http://dx.doi.org/10.1080/10428194.2019.1703974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115828PMC
May 2020

Mast Cell Activation: When the Whole Is Greater than the Sum of Its Parts.

Med Clin North Am 2020 Jan;104(1):177-187

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. Electronic address:

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.
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http://dx.doi.org/10.1016/j.mcna.2019.09.002DOI Listing
January 2020

Idiopathic anaphylaxis yardstick: Practical recommendations for clinical practice.

Ann Allergy Asthma Immunol 2020 01 9;124(1):16-27. Epub 2019 Sep 9.

Departments of Medicine and Pediatrics, Divisions of Allergy and Immunology, University of Tennessee, Memphis, Tennessee. Electronic address:

Anaphylaxis is considered idiopathic when there is no known trigger. The signs and symptoms of idiopathic anaphylaxis (IA) are identical to those of anaphylaxis because of a known cause and can include cutaneous, circulatory, respiratory, gastrointestinal, and neurologic symptoms. Idiopathic anaphylaxis can be a frustrating disease for patients and health care providers. Episodes are unpredictable, and differential diagnosis is challenging. Current anaphylaxis guidelines have little specific guidance regarding differential diagnosis and long-term management of IA. Therefore, the objective of the Idiopathic Anaphylaxis Yardstick is to use published data and the authors' combined clinical experience to provide practical recommendations for the diagnosis and management of patients with IA.
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http://dx.doi.org/10.1016/j.anai.2019.08.024DOI Listing
January 2020

AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management.

J Allergy Clin Immunol 2019 10 30;144(4):883-896. Epub 2019 Aug 30.

Department of Internal Medicine, Division of Rheumatology, Allergy and Immunology, Virginia Commonwealth University, Richmond, Va. Electronic address:

Our current recommendations for diagnosing and treating primary mast cell (MC) activation syndrome make use of the latest studies and consensus guidelines for clinically recognizing systemic anaphylaxis in real time, regardless of whether allergen-triggered or other pathways are involved; our current understanding of the biomarkers secreted by activated MCs that best discriminate this disorder from other conditions; and the therapeutic drugs that might selectively affect those mediators or MCs themselves. Finding familial or somatic mutations of genes that cause MCs to be hyperactivatable would extend our diagnostic tools and potentially indicate new therapeutic interventions, targeting either the mutated gene product or the associated molecular pathway. In conclusion, we trust that the clinical, laboratory, and therapeutic criteria for primary MC activation syndromes described herein will provide clinicians with practical criteria of sufficient sensitivity and specificity to diagnose most cases without overdiagnosing the disorder in patients who likely have other conditions.
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http://dx.doi.org/10.1016/j.jaci.2019.08.023DOI Listing
October 2019

Venom immunotherapy in patients with clonal mast cell disorders: IgG4 correlates with protection.

Allergy 2020 01 12;75(1):169-177. Epub 2019 Aug 12.

Department of Respiratory Medicine and Allergy, Karolinska University Hospital Huddinge, Stockholm, Sweden.

Background: Patients with clonal mast cell disorders (cMCD), systemic mastocytosis (SM) and monoclonal mast cell activation syndrome (MMAS), represent an increased risk for Hymenoptera venom anaphylaxis (HVA). Lifelong venom immunotherapy (VIT) is recommended; however, its efficacy and safety are controversial. Hence, we sought to evaluate the efficacy and safety of VIT in HVA patients with cMCD.

Methods: A retrospective study was conducted among 46 patients with Vespula venom allergy who had experienced severe HVA, 32 cMCD (22 with SM and 10 with MMAS) and 14 controls. There were no differences between cMCD patients and controls in age (58 vs 66) and duration of VIT (47 vs 48 months), respectively.

Results: During VIT, 11 (34%) cMCD patients experienced adverse reactions (ARs) (7% in controls), including 1 anaphylaxis. There were 23 re-stings in 17 (53%) patients during VIT. Of episodes, four (17%) presented with anaphylaxis, 14 (60%) presented with local reaction, and five (23%) were asymptomatic. In 11 episodes (48%), the patient did not take epinephrine, of these 8 (73%) presented with local reaction, and 3 (27%) were asymptomatic. Patient-based protection from anaphylaxis was 76% (4/17) in cMCD vs. 100% in controls during VIT. The venom-specific IgG4 concentrations increased during VIT (P < .001) although tryptase and IgE were unaltered.

Conclusion: Both safety and efficacy of VIT in cMCD patients were slightly reduced than controls. Severe ARs were rare. The elevated IgG4 levels may be a biomarker for efficacy of VIT in cMCD patients, as it correlates with protection from re-stings.
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http://dx.doi.org/10.1111/all.13980DOI Listing
January 2020

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 28;180(1):44-51. Epub 2019 Jun 28.

Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, Michigan, USA.

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.
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http://dx.doi.org/10.1159/000501079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115850PMC
September 2019

Multidisciplinary Challenges in Mastocytosis and How to Address with Personalized Medicine Approaches.

Int J Mol Sci 2019 Jun 18;20(12). Epub 2019 Jun 18.

Division of Allergy and Clinical Immunology, University of Salerno, 84131 Salerno, Italy.

Mastocytosis is a hematopoietic neoplasm defined by abnormal expansion and focal accumulation of clonal tissue mast cells in various organ-systems. The disease exhibits a complex pathology and an equally complex clinical behavior. The classification of the World Health Organization (WHO) divides mastocytosis into cutaneous forms, systemic variants, and localized mast cell tumors. In >80% of patients with systemic mastocytosis (SM), a somatic point mutation in at codon 816 is found. Whereas patients with indolent forms of the disease have a normal or near-normal life expectancy, patients with advanced mast cell neoplasms, including aggressive SM and mast cell leukemia, have a poor prognosis with short survival times. In a majority of these patients, multiple somatic mutations and/or an associated hematologic neoplasm, such as a myeloid leukemia, may be detected. Independent of the category of mastocytosis and the serum tryptase level, patients may suffer from mediator-related symptoms and/or osteopathy. Depending on the presence of co-morbidities, the symptomatology in such patients may be mild, severe or even life-threatening. Most relevant co-morbidities in such patients are IgE-dependent allergies, psychiatric, psychological or mental problems, and vitamin D deficiency. The diagnosis and management of mastocytosis is an emerging challenge in clinical practice and requires vast knowledge, a multidisciplinary approach, and personalized medicine procedures. In this article, the current knowledge about mastocytosis is reviewed with special emphasis on the multidisciplinary aspects of the disease and related challenges in daily practice.
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http://dx.doi.org/10.3390/ijms20122976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627900PMC
June 2019

The Role of KIT Mutations in Anaphylaxis.

Curr Allergy Asthma Rep 2019 04 26;19(6):31. Epub 2019 Apr 26.

Department of Internal Medicine, Division of Allergy and Immunology, University of Michigan, 24 Frank Lloyd Wright Drive, Suite H-2100, PO Box 442, Ann Arbor, MI, 48106-0442, USA.

Purpose Of Review: Gain of function KIT mutations are detected in clonal mast cell diseases, namely mastocytosis and monoclonal mast cell activation syndrome. Timely diagnosis and treatment of these disorders are crucial because of their association with severe and life-threatening anaphylaxis. KIT mutations also have implications for targeted therapies of mast cell disorders. This review article strives to serve as an overview of the role of clonal mast cell disorders in anaphylaxis while elucidating current and future therapies.

Recent Findings: Clonal mast cell disease has been increasingly diagnosed in patients with severe hymenoptera allergy and those with recurrent unexplained anaphylaxis. The current state of knowledge of the epidemiology, pathophysiology, diagnosis, and treatment of mastocytosis with a particular focus on anaphylaxis and its triggers which are described in this context. Novel and forthcoming treatments are discussed including the relevance of KIT mutation status. This review provides an overview of the role of KIT mutations in mastocytosis and anaphylaxis, and highlights emerging therapies for mastocytosis, targeting these mutations.
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http://dx.doi.org/10.1007/s11882-019-0863-5DOI Listing
April 2019

Blisters, Vaccines, and Mast Cells: A Difficult Case of Diffuse Cutaneous Mastocytosis.

J Allergy Clin Immunol Pract 2019 04;7(4):1370-1372

Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham, and Women's Hospital, Harvard Medical School, Boston, Mass.

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http://dx.doi.org/10.1016/j.jaip.2018.11.046DOI Listing
April 2019

Doctor, I Think I Am Suffering from MCAS: Differential Diagnosis and Separating Facts from Fiction.

J Allergy Clin Immunol Pract 2019 04;7(4):1109-1114

Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, Mich.

Mast cell activation syndrome (MCAS) is a rare condition defined by a severe systemic reaction to mast cell (MC)-derived mediators. Most cases present with clinical signs of anaphylaxis, and some have an underlying IgE-dependent allergy. A primary MC disease (mastocytosis) may also be detected. Severe recurrent MCAS episodes requiring intensive care or even resuscitation are typically found in patients who suffer from both mastocytosis and allergy against certain triggers, such as hymenoptera venom components. A less severe form and a local form of MC activation (MCA) also exist. For these patients, diagnostic criteria are lacking. Moreover, a number of different, unrelated, conditions with overlapping symptoms may be confused with MCAS. As a result, many patients believe that they are suffering from MCAS but have in fact a less severe form of MCA or another underlying disease. In the current article, we review the potential differential diagnoses of MCA and MCAS and discuss available diagnostic criteria and diagnostic tools. These criteria and assays may be useful in daily practice and help avoid unnecessary referrals and unjustified fears in patients.
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http://dx.doi.org/10.1016/j.jaip.2018.11.045DOI Listing
April 2019

Proposed Diagnostic Algorithm for Patients with Suspected Mast Cell Activation Syndrome.

J Allergy Clin Immunol Pract 2019 04 5;7(4):1125-1133.e1. Epub 2019 Feb 5.

Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.

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.
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http://dx.doi.org/10.1016/j.jaip.2019.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643056PMC
April 2019

Toward a Unified Database Registry in Mastocytosis.

J Allergy Clin Immunol Pract 2019 01;7(1):88

Department of Internal Medicine, Division of Allergy, Mayo Clinic, Rochester, Minn.

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http://dx.doi.org/10.1016/j.jaip.2018.11.001DOI Listing
January 2019

Diffuse cutaneous mastocytosis with novel somatic KIT mutation K509I and association with tuberous sclerosis.

Clin Case Rep 2018 Sep 31;6(9):1834-1840. Epub 2018 Jul 31.

Pediatric Allergy & Immunology Massachusetts General Hospital Boston MA USA.

Diffuse cutaneous mastocytosis (DCM) is a rare but potentially fatal condition when diagnosis and targeted treatments are delayed. This case illustrates the life-threatening complications in DCM and reviews the currently available treatments. To our knowledge, this is the first report of mastocytosis with somatic K509I mutation and concomitant tuberous sclerosis.
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http://dx.doi.org/10.1002/ccr3.1607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132108PMC
September 2018

Core-binding factor acute myeloid leukemia with t(8;21): Risk factors and a novel scoring system (I-CBFit).

Cancer Med 2018 09 16;7(9):4447-4455. Epub 2018 Aug 16.

Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas.

Background: Although the prognosis of core-binding factor (CBF) acute myeloid leukemia (AML) is better than other subtypes of AML, 30% of patients still relapse and may require allogeneic hematopoietic cell transplantation (alloHCT). However, there is no validated widely accepted scoring system to predict patient subsets with higher risk of relapse.

Methods: Eleven centers in the US and Europe evaluated 247 patients with t(8;21)(q22;q22).

Results: Complete remission (CR) rate was high (92.7%), yet relapse occurred in 27.1% of patients. A total of 24.7% of patients received alloHCT. The median disease-free (DFS) and overall (OS) survival were 20.8 and 31.2 months, respectively. Age, KIT D816V mutated (11.3%) or nontested (36.4%) compared with KIT D816V wild type (52.5%), high white blood cell counts (WBC), and pseudodiploidy compared with hyper- or hypodiploidy were included in a scoring system (named I-CBFit). DFS rate at 2 years was 76% for patients with a low-risk I-CBFit score compared with 36% for those with a high-risk I-CBFit score (P < 0.0001). Low- vs high-risk OS at 2 years was 89% vs 51% (P < 0.0001).

Conclusions: I-CBFit composed of readily available risk factors can be useful to tailor the therapy of patients, especially for whom alloHCT is not need in CR1 (ie, patients with a low-risk I-CBFit score).
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http://dx.doi.org/10.1002/cam4.1733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144246PMC
September 2018

The Mastocytosis Society Survey on Mast Cell Disorders: Part 2-Patient Clinical Experiences and Beyond.

J Allergy Clin Immunol Pract 2019 04 8;7(4):1157-1165.e6. Epub 2018 Aug 8.

Department of Internal Medicine, Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, Mich. Electronic address:

Background: Mast cell diseases such as mastocytosis and mast cell activation syndrome involve abnormal proliferation and/or activation of these cells, leading to many clinically relevant symptoms.

Objective: To determine the characteristics and experiences of people known or suspected to have a mast cell disorder, The Mastocytosis Society, a US-based patient advocacy, research, and education organization, conducted a survey of patients.

Methods: This Web-based survey was publicized through specialty clinics and the society's newsletter, Web site, and online blogs. Both online and paper copies of the questionnaire were provided together with required statements of consent.

Results: The first set of results from this survey of 420 respondents has been previously published; the second set is presented in this article. These results include source(s) of diagnosis, clinical and laboratory tests reported, comorbidities, dietary practices, possible familial occurrence of mast cell disorders, and perceptions concerning mast cell disorder-related medical care needs in the United States.

Conclusions: These patient survey results are provided to assist medical professionals in learning patients' perceptions of their experiences and to give patients with mast cell disorders and caregivers the opportunity to compare experiences with those of other affected individuals.
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http://dx.doi.org/10.1016/j.jaip.2018.07.032DOI Listing
April 2019

New Insights into Clonal Mast Cell Disorders Including Mastocytosis.

Immunol Allergy Clin North Am 2018 08 9;38(3):341-350. Epub 2018 Jun 9.

Division of Allergy and Clinical Immunology, Department of Internal Medicine, University of Michigan, 24 Frank Lloyd Wright Drive, PO Box 442, Suite H-2100, Ann Arbor, MI 48106-0442, USA. Electronic address:

Mastocytosis is a heterogeneous group of neoplasms that involve the clonal expansion of mast cells into one or more organ systems, which typically involves the skin and hematopoietic systems. Systemic mastocytosis consists of a multifocal infiltration of mast cells into various noncutaneous tissue sites, especially the bone marrow. Diagnosis requires tissue confirmation, and algorithms have been developed to assist clinicians in this process. The current classification system focuses on delineating prognostic categories. Therapeutic approaches include symptomatic management, prevention of complications, and, in advanced disease, cytoreductive therapy.
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http://dx.doi.org/10.1016/j.iac.2018.04.014DOI Listing
August 2018

Preclinical human models and emerging therapeutics for advanced systemic mastocytosis.

Haematologica 2018 11 5;103(11):1760-1771. Epub 2018 Jul 5.

Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria.

Mastocytosis is a term used to denote a group of rare diseases characterized by an abnormal accumulation of neoplastic mast cells in various tissues and organs. In most patients with systemic mastocytosis, the neoplastic cells carry activating mutations in Progress in mastocytosis research has long been hindered by the lack of suitable models, such as permanent human mast cell lines. In fact, only a few human mast cell lines are available to date: HMC-1, LAD1/2, LUVA, ROSA and MCPV-1. The HMC-1 and LAD1/2 cell lines were derived from patients with mast cell leukemia. By contrast, the more recently established LUVA, ROSA and MCPV-1 cell lines were derived from CD34 cells of non-mastocytosis donors. While some of these cell lines (LAD1/2, LUVA, ROSA and MCPV-1) do not harbor mutations, HMC-1 and ROSA cells exhibit activating mutations found in mastocytosis and have thus been used to study disease pathogenesis. In addition, these cell lines are increasingly employed to validate new therapeutic targets and to screen for effects of new targeted drugs. Recently, the ROSA subclone has been successfully used to generate a unique model of advanced mastocytosis by injection into immunocompromised mice. Such a model may allow validation of data obtained with targeted drugs directed against mastocytosis. In this review, we discuss the major characteristics of all available human mast cell lines, with particular emphasis on the use of HMC-1 and ROSA cells in preclinical therapeutic research in mastocytosis.
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http://dx.doi.org/10.3324/haematol.2018.195867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278969PMC
November 2018