Indolent systemic mastocytosis with elevated serum tryptase, absence of skin lesions, and recurrent severe anaphylactoid episodes

BACKGROUND: In contrast to aggressive mastocytosis, patients with indolent systemic mastocytosis (ISM) usually present with urticaria pigmentosa-like skin lesions. In those who lack skin lesions, mastocytosis is often overlooked or confused with endocrinologic, allergic, or other internal disorders. CASE REPORT AND RESULTS: We report on a 33-year-old male patient in whom severe hypotensive episodes occurred after contact with ants or yellow jackets. Since no specific IgE was detected, the serum tryptase concentration was measured and found to be clearly elevated (70 ng/ml). Consecutive staging and examination of the bone marrow revealed ISM. The patient was advised to circumvent insect contact, to take antihistamines on demand, and to carry an epinephrine self-injector for emergency events. In a retrospective analysis of 40 patients seen between 1988 and 2003, only 2 had a life-threatening mediator-related episode before ISM was diagnosed. CONCLUSIONS: Our report confirms the diagnostic value of tryptase in patients with suspected mastocytosis. In addition, the report suggests that the lack of typical skin lesions does not exclude an indolent form of mastocytosis even if the serum tryptase is clearly elevated. Finally, our case further shows that mastocytosis can be an important differential diagnosis to be considered in patients with unexplained anaphylactoid or other mediator-related symptoms.     

Mast cell mediators in allergic inflammation and mastocytosis

Mast cells possess an array of potent inflammatory mediators capable of inducing acute symptoms after cell activation, including urticaria, angioedema, bronchoconstriction, diarrhea, vomiting, hypotension, cardiovascular collapse, and death in few minutes. In contrast, mast cells can provide an array of beneficial mediators in the setting of acute infections, cardiovascular diseases, and cancer. The balance between the detrimental and beneficial roles of mast cells is not completely understood. Although the symptoms of acute mast cell mediator release can be reversed with epinephrine, adrenergic agonists, and mediator blockers, the continued release of histamine, proteases, prostaglandins, leukotrienes, cytokines, and chemokines leads to chronic and debilitating disease, such as mastocytosis. Identification of the molecular factors and mechanisms that control the synthesis and release of mast cell mediators should benefit all patients with mast cell activation syndromes and mastocytosis.     

Anaphylaxis: a review of 601 cases.

BACKGROUND: The allergist usually sees patients with anaphylaxis after the event for the purposes of identifying the cause, establishing a prognosis, and preventing further episodes. Knowledge of the characteristics of such patients is essential to achieve these goals. OBJECTIVE: To examine the natural history, clinical manifestations, and factors that affect the patients' adherence to suggested treatment and preventive strategies of anaphylaxis. METHODS: A retrospective medical record review spanning 25 years (1978-2003) and follow-up questionnaires were used to obtain data on 601 patients who presented with anaphylaxis of unknown origin to a private university-affiliated allergy-immunology practice. RESULTS: Patients ranged in age from 1 to 79 years, with a mean age of 37 years. Females comprised 62% of cases. Causes of anaphylaxis were elucidated in 41% of cases. Known causes included foods in 131 patients (22%), medications in 69 cases (11%), and exercise in 31 cases (5%). Two hundred twenty-three patients (37%) were found to be atopic by history confirmed with skin prick testing. The most common manifestation was urticaria and/or angioedema, reported in 87% of patients. Systemic mastocytosis was found in 3 patients. Episodes tended to decline in frequency with time. Adherence to instructions to carry epinephrine can be improved with more effective teaching. CONCLUSIONS: In most cases, the cause of anaphylaxis is undetermined. Women are affected more commonly than men. Systemic mastocytosis should be considered in cases of idiopathic anaphylaxis, and patients with a history of atopy are at an increased risk of developing anaphylaxis. Patients are more reliably carrying epinephrine as a result of changes in physician instructions. Finally, anaphylactic episodes tend to decrease in frequency and severity with time.     

Mastocytosis and allergy

PURPOSE OF REVIEW: To illustrate features of allergy in mastocytosis. RECENT FINDINGS: The rates of atopy in patients with mastocytosis have generally been found to be similar to those of the normal population, although the incidence of anaphylaxis is much higher in mastocytosis. Introduction of objective pathologic criteria by the WHO for the diagnosis of mastocytosis has greatly facilitated the workup of patients with suspected mastocytosis, and has led to identification of mast cell disease in a subset of patients with anaphylaxis. There is increasing evidence that an activating c-kit mutation (D816V) exists in a subset of patients with recurrent mast cell activation symptoms who have normal-appearing bone marrow biopsies in routine evaluations without skin lesions. The genetic deficiency of alpha tryptase has not been found to influence serum tryptase levels in patients with mastocytosis. SUMMARY: Pathologic mast cell activation is a key finding in both allergic diseases and mastocytosis, albeit caused by entirely different mechanisms. Mastocytosis should be suspected in patients with recurrent anaphylaxis, who present with syncopal or near-syncopal episodes without associated hives or angioedema.     

Anaphylaxis after hymenoptera stings in three patients with urticaria pigmentosa

Three patients with urticaria pigmentosa are reported who developed symptoms of anaphylaxis after Hymenoptera stings. Serum IgE antibodies to various Hymenoptera venoms could not be detected in any of the patients. Skin tests were completely negative in one patient, and borderline reactions with honeybee and yellow jacket venom, respectively, were found in the other two. Peripheral blood leukocytes of these latter two patients did not release significant amounts of histamine after exposure to the respective venoms. In patients with mastocytosis, anaphylaxis after insect stings may not be IgE-mediated but due to mediator release by the pharmacologic action of histamine liberators normally present in Hymenoptera venoms.     

Failure of sulfites to produce clinical responses in patients with systemic mastocytosis or recurrent anaphylaxis: Results of a single-blind study

Although sulfite sensitivity can precipitate asthma in a subpopulation of subjects with asthma, its role in precipitating anaphylaxis or as a nonspecific mast cell degranulator in systemic mastocytosis has not been examined. To evaluate critically the importance of sulfites in these diseases, eight patients with systemic mastocytosis and 25 patients with unexplained, recurrent anaphylaxis were challenged in a single-blind fashion; sodium bisulfite in capsules was administered in increasing doses of 1, 5, 10, 25, 50, 100, and 200 mg every 30 minutes. On separate occasions a liquid suspension of 200 mg of sodium bisulfite was administered to one patient with systemic mastocytosis and nine patients with anaphylaxis. Vital signs, pulmonary function tests, plasma histamine levels, and clinical reactions were monitored. There were no observable responses in either the mastocytosis group or in 23 of 25 patients in the anaphylaxis group. Two patients in the anaphylaxis group with initial positive challenges had similar symptoms on subsequent placebo challenge. One subject with asthma and with a history suggestive of sulfite sensitivity responded to oral challenge with 5 mg of sodium bisulfite and 100 micrograms of sodium bisulfite intradermally with a dramatic reduction in FEV, requiring treatment with bronchodilators. A comparison of baseline plasma histamine levels with those obtained after the sulfite challenge procedure in each category demonstrated a significant rise (p less than 0.05) in the systemic mastocytosis group. The overall level of significance determined by applying paired sample t tests to the histamine data from all subjects was p less than 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)     

Contemporary Challenges in Mastocytosis

Mastocytosis denotes a wide range of disorders characterized by having abnormal growth and accumulation of mast cells. Mast cells contain histamine and other inflammatory mediators, which have diverse actions within the body, and play crucial roles in acquired and innate immunity. The diverse actions of these inflammatory mediators can lead to puzzling symptoms in individuals with mastocytosis. These symptoms can include flushing, pruritis, nausea, vomiting, abdominal pain, diarrhea, vascular instability, and headache. These clinical features generally divide into cutaneous and systemic manifestations, giving rise to the two divisions of mastocytosis: cutaneous mastocytosis (CM) and systemic mastocytosis. CM has a highly favorable clinical prognosis. Systemic mastocytosis has a range of severity, with the milder forms often remaining chronic conditions, while the severe forms have rapid complex courses with poor prognoses. Generally, treatment is aimed at avoiding mast cell degranulation, inhibiting the actions of the constitutive mediators released by mast cells and, in severe cases, cytoreductive and polychemotherapeutic agents. Behavioral intervention includes avoidance of triggers, such as heat, cold, pressure, exercise, sunlight, and strong emotions. Treatment for released histamine and other inflammatory mediators includes H1 antihistamines, H2 antihistamines, proton pump inhibitors, anti-leukotriene agents, and injectible epinephrine (for possible anaphylaxis). For severe cases, treatment includes cytoreductive agents (interferon alpha, glucocorticoids, and cladribine) and polychemotherapeutic agents (daunomycin, etoposide, and 6-mercaptopurine). For very specific and severe cases, tyrosine kinase inhibitors, imatinib and midostaurine, have shown promise.     

Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: Monoclonal mast cell activation syndrome

BACKGROUND: Patients with mastocytosis may suffer from severe hypotension after wasp or bee stings. In these patients, no specific IgE is detectable, but they usually have skin lesions and an elevated serum tryptase level. METHODS: We report on 6 patients who were referred to our department because of severe hypotension following bee or wasp stings without cutaneous lesions. RESULTS: In 3 patients, the baseline serum tryptase level was elevated (26, 36, and 67 ng/ml, respectively), and investigation of their bone marrow revealed systemic mastocytosis (SM). In the remaining 3 patients, serum tryptase levels were <20 ng/ml, and bone marrow histology and tryptase immunohistochemistry did not reveal diagnostic mast cell infiltrates. However, in 1 patient, three minor SM criteria were demonstrable leading to the diagnosis SM, and in the 2nd patient, two minor SM criteria, including an aberrant mast cell phenotype, were found. In the 3rd patient, no minor SM criteria were detected. CONCLUSIONS: All patients with unexplained hypotension after hymenoptera stings should undergo a thorough investigation for major and minor SM criteria regardless of the tryptase level or presence of skin lesions, in order to diagnose or exclude SM or a related subdiagnostic condition (1 or 2 minor SM criteria) tentatively termed monoclonal mast cell activation syndrome.     

Occurrence of platelet-activating factor (PAF) and an endogenous inhibitor of platelet aggregation in diffuse cutaneous mastocytosis.

We have identified PAF in the blister fluid from a patient with bullous mastocytosis, a rare form of mast-cell disease. We have found a novel endogenous inhibitor of platelet aggregation which obscured the presence of the PAF in unprocessed blister fluid and in ethanol or lipid extracts. The PAF was characterized by the demonstration of chromatographic, mass spectral and biological properties identical to those of authentic PAF. Thus this is the first demonstration of PAF in biological fluid from a patient with mastocytosis. High levels of immunoreactive prostaglandin D2 (PGD2) and histamine were also present in the blister fluid. The interaction between PAF and the inhibitor of platelet aggregation in patients with systemic mastocytosis may provide an explanation for some of the manifestations of the disease, in particular the episodic hypotension, cutaneous flushing and pallor.     

Metoclopramide alone or combined with flurbiprofen in the treatment of orthostatic hypotension associated with diabetes mellitus

Summary Two patients with orthostatic hypotension, complicating diabetes mellitus, were treated with the dopaminergic antagonist metoclopramide alone or combined with the nonsteroidal anti-inflammatory agent flurbiprofen. Both patients responded favorably to combined treatment of both drugs, with improvement of orthostatic hypotension. In one case, this improvement persisted after withdrawal of flurbiprofen on metoclopramide monotherapy. Blood volume and plasma aldosterone, norepinephrine, and epinephrine levels were unaltered during treatment with these agents. However, plasma renin activity was markedly decreased and, in one patient, exchangeable sodium was increased by 250 mmol. Metoclopramide, alone or combined with the nonsteroidal agent flurbiprofen, may be useful in the treatment of postural hypotension associated with diabetes mellitus. The favorable influence of these agents on blood pressure could not be explained by blood volume expansion or activation of the sympathetic or renin-angiotensinaldosterone systems.This work was supported by the Swiss National Science Foundation     

Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients

Background:  Excessive mast cell mediator release may lead to anaphylaxis in patients with mastocytosis. However, the incidence, clinical features and trigger factors have not yet been analyzed.
Methods:  To identify risk factors for anaphylaxis in mastocytosis, we determined cumulative incidence, severity, clinical characteristics, and trigger factors for anaphylaxis in 120 consecutive patients (53 male; 67 female, median age and range 24 years, 1 month to 73 years), and correlated these with disease severity of mastocytosis, skin involvement, basal total serum tryptase, and diaminooxidase concentrations.
Results:  The cumulative incidence of anaphylaxis in patients with mastocytosis was higher in adults (49%; P  < 0.01) compared with that in children (9%). Only children with extensive skin involvement had experienced anaphylaxis. In adults, anaphylaxis was correlated to the absence of urticaria pigmentosa lesions ( P  < 0.03). Reactions occurred more frequently in adults with systemic (56%) when compared with cutaneous mastocytosis (13%; P  < 0.02). In adults, 48% of reactions were severe, and 38% resulted in unconsciousness. Major perceived trigger factors for adults were hymenoptera stings (19%), foods (16%), and medication (9%); however, in 26% of reactions, only a combination of different triggers preceded anaphylaxis. Trigger factors remained unidentified in 67% of reactions in children compared with 13% in adults. Patients with anaphylaxis had higher basal tryptase values (60.2 ± 55 ng/ml, P  < 0.0001) in comparison with those without (21.2 ± 33 ng/ml), but not diaminooxidase levels.
Conclusion:  Adult patients and children with extensive skin disease with mastocytosis have an increased risk to develop severe anaphylaxis; thus, an emergency set of medication including epinephrine is recommended.     

Cardiovascular aspects of anaphylaxis: implications for treatment and diagnosis

PURPOSE OF REVIEW: Anaphylactic cardiovascular collapse can be resistant to treatment with epinephrine (adrenaline) and, in some cases, diagnostic uncertainty compromises follow-up care. The purpose of this review is to examine recent studies relevant to the management and diagnosis of this condition. RECENT FINDINGS: Nausea, vomiting, incontinence, diaphoresis, dyspnoea, hypoxia, dizziness and collapse are associated with hypotension. Relative bradycardia (falling heart rate despite hypotension) is a consistent feature of hypotensive insect sting anaphylaxis and may represent a non-specific physiological response to severe hypovolaemia in conscious individuals. Upright posture has been found to be associated with death from anaphylaxis. Animal studies have found the intramuscular route for epinephrine is ineffective, intravenous boluses temporarily effective, but intravenous infusions of epinephrine are able to reverse anaphylactic shock. In one animal model, antihistamines were found to be harmful. A prospective human study provides evidence for the efficacy of treatment with intravenous epinephrine infusion and fluid (volume) resuscitation. Case reports support the use of the vasoconstrictors metaraminol, methoxamine and vasopressin if adrenaline is ineffective. Repeated measurements of mast cell tryptase are more sensitive and specific than a single measurement for the diagnosis of anaphylaxis. SUMMARY: Current evidence supports use of the supine/Trendelenburg position, epinephrine by intravenous infusion and aggressive volume resuscitation. If these fail, atropine should be considered for severe bradycardia and potent vasoconstrictors may be useful. To confirm the diagnosis of anaphylaxis, serial measurements of mast cell tryptase may be preferable to a single measurement.     

Risk factors and management of severe life‐threatening anaphylaxis in patients with clonal mast cell disorders

Several different risk factors and conditions may predispose to severe life‐threatening anaphylaxis. Systemic mastocytosis (SM) is one such condition. Although many SM patients are suffering from mild or even no mediator‐related symptoms, others have recurrent episodes of severe anaphylaxis, with clear signs of a mast cell activation syndrome (MCAS) despite prophylactic therapy with anti‐mediator‐type drugs. In several of these patients, an IgE‐dependent allergy is diagnosed. The severity and frequency of MCAS reactions neither correlate with the burden of neoplastic mast cells nor with the levels of specific IgE or the basal tryptase level. However, there is a relationship between severe anaphylaxis in SM and the type of allergen. Notably, many of these patients suffer from hymenoptera venom allergy. Currently recommended therapies include the prophylactic use of anti‐mediator‐type drugs, long‐term immunotherapy for hymenoptera venom allergic patients, and epinephrine‐self‐injector treatment for emergency situations. In patients who present with an excess burden of mast cells, such as smouldering SM, cytoreductive therapy with cladribine (2CdA) may reduce the frequency of severe events. For the future, additional treatment options, such as IgE‐depletion or the use of tyrosine kinase inhibitors blocking IgE‐dependent mediator secretion as well as KIT activation, may be useful alternatives.     

Clinical varieties of mastocytoses

Varieties of the clinical features of mastocytoses, also called mastocytosis syndrome, are presented. The disease is characterized by excessive accumulation of mast cells, their proliferation and action in the skin and other organs, even in the central nervous system. The mastocytosis syndrome was known as early as the second half of the 19th century under the term urticaria pigmentosa, and was histologically confirmed by the presence in the dermis of metachromatic cells, i.e. Ehrlich mast cells with red-purple cytoplasmic granules visible with Giemsa or toluidine blue stains. The mastocytosis syndrome was then supposed to be a benign chronic dermatosis of childhood with spontaneous regression by adolescence. The clinically pathognomonic symptoms of Darier's sign (urtication of primary skin lesion upon rubbing) and flushing help in the diagnosis of mastocytosis syndrome. In the 1950s, there was a progression in the diagnosis of systemic mastocytosis achieved by scientists and clinicians of various specialties. Upon the discovery of many mast cell released mediators (heparin, histamine, leukotrienes, prostaglandins, proteases, cytokines), receptor functions, relationship to IgE, anaphylatoxin, etc., they were recognized as triggers of various clinical features of the mastocytosis syndrome. In this paper, different forms of cutaneous and systemic mastocytosis are described, with special reference to 'mastocytosis mucocutanea haemorrhagica' observed by one of the authors in a female infant and followed from 6 months till 2.5 years of age. The patient showed practically all the diverse forms of cutaneous mastocytosis: urticaria pigmentosa, papular, nodular, tumorous-like melanoma, vesiculobullous, erythrodermic, telangiectasia eruptiva maculosa perstans. She also suffered from nasal and rectal hemorrhage, conjunctival suggillations, plaque-like infiltrations of the glossal, oropharyngeal and laryngotracheal mucosa, episodes of flushing, and transitory apnea. It is emphasized that the diagnosis of mastocytosis syndrome may be difficult for its mimicking various other diseases. The occurence of mastocytosis syndrome from the neonatal period through adult and old age, and possibilities of symptomatic treatment and prevention of sudden death or fatalities are discussed. Familial occurrence of mastocytosis syndrome and new genetic studies that may prove highly useful for understanding the etiopathogenesis of mastocytosis syndrome are described.     

Systemic mastocytosis with associated myeloproliferative neoplasm with t(8;19)(p12;q13.1) and abnormality of FGFR1: report of a unique case

Systemic mastocytosis is a neoplastic proliferation of mast cells that frequently presents with associated clonal hematological non-mast cell lineage disease. Myeloid and lymphoid neoplasms with abnormalities of the FGFR1 gene are a heterogenous group of rare and aggressive hematopoietic stem cell disorders. About a dozen of chromosome changes involving the FGFR1 gene, presenting as myeloid or lymphoid neoplasms, have been described in the literature. To date, only 2 cases of myeloid and lymphoid neoplasms with abnormalities of the FGFR1 gene have been reported in association with systemic mastocytosis, one with t(8;13) and one with t(8;17) involving the FGFR1 gene. Here we describe another case of myeloproliferative neoplasm with chromosome translocation t(8;19) involving FGFR1 gene associated with systemic mastocytosis.     

Decreased tryptophan and increased kynurenine levels in mastocytosis associated with digestive symptoms

The main metabolism pathway of tryptophan is protein formation, but it can also be metabolized into serotonin and kynurenine. Indoleamine 2,3‐dioxygenase (IDO) is the enzyme that catalyzes the degradation of tryptophan into kynurenine. Mastocytosis is a heterogeneous disease characterized by mast cell accumulation in various tissues with 57% of patients having gastrointestinal involvement. We studied tryptophan metabolism in mastocytosis patients displaying or not gastrointestinal features and healthy subjects (n = 26 in each group). Mastocytosis patients with digestive symptoms displayed significantly increased kynurenine level and IDO activity as compared to healthy controls and mastocytosis patients without digestive symptoms. This could be linked to mast cell‐mediated digestive inflammation among patients with mastocytosis. This work is the first focusing on kynurenine pathway in a mast cell disease and could help to understand the pathogenesis of digestive features in mastocytosis as well as in other mast cell‐mediated diseases.     

A Case of Anaphylaxis to Oral Minocycline

Minocycline is a semisynthetic tetracycline derivative that is often used in the treatment of acne vulgaris. To date, there has been only one case report of anaphylaxis to minocycline. We report here a case of anaphylaxis to oral minocycline. A 56-yr-old woman visited our hospital after three episodes of recurrent anaphylaxis. We performed an oral challenge test, the standard method for diagnosing drug allergies, with minocycline, one of the drugs she had taken previously. She developed urticaria, angioedema, nausea, vomiting, hypotension, and dyspnea within 4 min and was treated with intramuscular epinephrine, intravenous antihistamine and systemic corticosteroid. However, she presented similar symptoms at 50 min and at 110 min. In prescribing oral minocycline, physicians should consider the possibility of serious adverse reactions, such as anaphylaxis.     

First-aid treatment of anaphylaxis to food: focus on epinephrine

Avoiding food triggers for anaphylactic reactions (severe acute systemic allergic reactions) is easier said than done. Most episodes of anaphylaxis to food occur unexpectedly in the community in the absence of a health care professional. All individuals at risk should therefore have an emergency action plan in place. The cornerstone of first-aid treatment of anaphylaxis is epinephrine injected intramuscularly in the vastus lateralis muscle (lateral aspect of the thigh). In this review, we focus on epinephrine. We examine a therapeutic dilemma: the issue of epinephrine dose selection in an individual for whom no optimal fixed-dose auto-injector formulation exists, and a therapeutic controversy: the issue of epinephrine injection versus an oral H1-antihistamine in anaphylaxis episodes that appear to be mild. The pharmaceutical industry could address the first of these issues by providing a wider range of epinephrine fixed doses in easy-to-use auto-injectors, or by providing adjustable epinephrine doses in auto-injectors. The second issue could be addressed in part by development of alternative routes of epinephrine administration for the first-aid, out-of-hospital treatment of anaphylaxis.     

A Case of Long QT Syndrome Type 3 Aggravated by Beta-Blockers and Alleviated by Mexiletine: The Role of Epinephrine Provocation Test

Long QT syndrome (LQTs) is an uncommon genetic disease causing sudden cardiac death with Torsade de Pointes (TdP). The first line drug treatment has been known to be β-blocker. We encountered a 15-year-old female student with LQTs who had prolonged QTc and multiple episodes of syncope or agonal respiration during sleep. Although her T wave morphology in surface electrocardiography resembled LQTs type 1, her clinical presentation was unusual. During the epinephrine test, TdP was aggravated during β-blocker medication, but alleviated by sodium channel blocker (mexiletine). Therefore, she underwent implantable cardioverter defibrillator implantation.     

Mast cells in cutaneous mastocytosis: accumulation of the MCTC type

Lesional (n = 15) and non-lesional (n = 10) skin of subjects with mastocytosis was analysed for the distribution and concentration of trypase positive, chymase negative mast cells (MCT) and tryptase positive, chymase positive mast cells (MCTC) cells and compared to normal skin (n = 23) and non-lesional skin of subjects with unexplained anaphylaxis or flushing episodes (n = 6). Skin biopsies were fixed in Carnoy's fluid and subjected to double immunohistochemical staining with biotinylated mouse monoclonal anti-chymase antibody followed by alkaline phosphatase-conjugated mouse monoclonal anti-tryptase antibody. MCTC cells were the only type of mast cells seen in all specimens analysed and in each case were more numerous in superficial compared to deep regions of dermis. The concentration (mean +/- s.d.) of mast cells in the superficial dermis of mastocytosis lesions (40 985 +/- 21 772 mast cells/mm3) was significantly increased over that in corresponding areas of non-lesional skin from subjects with mastocytosis (7178 +/- 3607 mast cells/mm3), skin from subjects with idiopathic anaphylaxis or flushing episodes (6974 +/- 3873 mast cells/mm3) and normal skin (7347 +/- 2973 mast cells/mm3). The exclusive presence of MCTC cells in skin lesions of mastocytosis which are characterized by non-malignant hyperplasia of mast cells suggests involvement of local tissue factors in mast cell recruitment and differentiation.