Grand Rounds Review
Anaphylaxis After Hymenoptera Sting: Is It Venom Allergy, a Clonal Disorder, or Both? Mariana C. Castells, MD, PhD, Jason L. Hornick, MD, PhD, and Cem Akin, MD, PhD A 47-year-old man presented with loss of consciousness 5 minutes after being stung by a yellow jacket in his backyard. Epinephrine and fluids were required for resuscitation. Allergy evaluation revealed specific IgE to yellow jacket and honeybee, and the patient was started on venom immunotherapy. He had systemic reactions during buildup and a severe anaphylactic episode requiring 3 doses of intramuscular epinephrine at maintenance doses. Immunotherapy was discontinued. Serum tryptase level after 1 such episode was 29 ng/mL, with a baseline level of 25 ng/mL 4 weeks later. The physical examination was unremarkable including no skin lesions of cutaneous mastocytosis. Because of elevated baseline tryptase level, a bone marrow biopsy was performed, which revealed multifocal dense infiltrates of mast cells. A diagnosis of systemic mastocytosis was made. The patient was treated with omalizumab and was able to tolerate immunotherapy and is currently maintained on lifelong immunotherapy. He was restung in the field and has not had anaphylaxis. Ó 2015 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2015;3:350-5) Key words: Mastocytosis
Mast
cells;
Hymenoptera;
c-kit
anaphylaxis. A bone marrow biopsy and aspiration should be considered for those with elevated baseline tryptase levels. Complications of systemic mastocytosis include osteopenia and osteoporosis, which can lead to bone fractures and can be prevented with early treatment. Progression to aggressive mastocytosis or an associated hematological malignancy can occur in a small subset of patients with systemic mastocytosis but has not been documented in patients presenting initially with hymenoptera anaphylaxis. A small number of patients can also have severe anaphylactic reactions to certain drugs (including nonsteroidal anti-inflammatory drugs, opioids, vancomycin, and muscle relaxants) and contrast dyes. Premedication regimens similar to those used in prophylaxis of contrast dye allergy have been proposed before medical procedures involving general anesthesia, although the efficacy of these regimens has not been systemically evaluated. Upper gastrointestinal irritation due to gastric acid hypersecretion is another common complication and can be prevented by the use of H2 antihistamines and proton pump inhibitors.
mutations;
The presentation, diagnosis, and molecular features of a subset of indolent systemic mastocytosis (ISM) associated with hymenoptera anaphylaxis are reviewed, and the approach to management and treatment is discussed. Patients with anaphylactic reactions to hymenoptera venom presenting with hypotension are at an increased risk for having systemic mastocytosis as the underlying diagnosis, modifying the severity of the presentation. A baseline serum tryptase level is recommended as a screening test for all patients with hymenoptera
Mastocytosis Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass Conflicts of interest: M. C. Castells is on the American Academy of Allergy, Asthma & Immunology Board; has received consultancy fees from Sanofi; is employed by Brigham and Women’s Hospital; has received research support from Ovations for the Cure; has received lecture fees from the Kansas Allergy Society; and receives royalties from UpToDate. C. Akin has received consultancy fees from Novartis, Patara Pharma, and Blueprint Medicines; is employed by Brigham and Women’s Hospital; and has a patent through the National Institutes of Health (LAD2 cell line). J. L. Hornick declares that he has no relevant conflicts of interest. Received for publication January 26, 2015; revised March 28, 2015; accepted for publication March 30, 2015. Available online April 7, 2015. Corresponding author: Mariana C. Castells, MD, PhD, Harvard Medical School, Brigham and Women’s Hospital, 1 Jimmy Fund Way, Smith Bldg, Rm 626D, Boston, MA 02115. E-mail: [email protected]. 2213-2198 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2015.03.015
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CLINICAL PRESENTATION A 47-year-old man working in his backyard was stung by a yellow jacket. He felt weak and dizzy with tunnel vision and lost consciousness within 5 minutes. Epinephrine was injected intramuscularly in the field, and he was brought to the emergency room. He received fluids, antihistamines, and glucocorticosteroids, and he recovered without sequelae. Evaluation by skin testing 6 weeks later was negative for all hymenoptera venoms, possibly due to the anergic period following anaphylaxis, but specific IgE was positive for yellow jacket (class II) and honeybee (class I). He was started on venom immunotherapy (VIT) with mixed vespids and honeybee at an outside allergy clinic. He had mild to moderate systemic reactions while receiving buildup doses, requiring several epinephrine injections, but was able to reach maintenance and started a program of 300 mg of mixed vespids and 100 mg of honeybee every 4 weeks. At the second injection of maintenance, he was 2 weeks late (6 weeks since his last injection) and had immediate tunnel vision, hypotension, oxygen desaturation, and loss of consciousness and required 3 doses of intramuscular epinephrine for resuscitation. A tryptase level (the exact timing was unclear but within 24 hours of the reaction) was found to be elevated at 29 ng/mL. Immunotherapy was discontinued, and the patient care was transferred to the Brigham and Women’s Hospital Mastocytosis Center. A tryptase baseline repeat level 4 weeks later was 25 ng/mL. The patient had a full-body skin examination that ruled out urticaria pigmentosa, mastocytoma, or other forms of cutaneous mastocytosis that could explain the elevation in the tryptase level. He had no organomegaly or lymphadenopathy. The patient had a history of allergic rhinitis
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Abbreviations used MMAS- Monoclonal mast cell activation syndrome VIT- Venom immunotherapy
and mild asthma and used over-the-counter antihistamines and bronchodilators intermittently. His review of systems was positive for frequent episodes of flushing associated with palpitations, abdominal bloating and pain, and intermittent diarrhea for the last 2 to 3 years. He complained of generalized bone pain and mild depression and anxiety. He denied food allergies and had not used oral steroids or been hospitalized for his asthma. A bone marrow biopsy was performed because of the baseline elevated tryptase level and showed small perivascular aggregates of mast cells including atypical spindle-shaped forms, which were positive for CD25 (Figure 1). The patient received a diagnosis of ISM. His bone marrow did not show evidence of myelodysplastic or myeloproliferative disorders, and his peripheral blood cell counts were within normal range without eosinophilia. His liver enzymes and metabolic panel were normal, and a bone densitometry was normal without evidence of osteopenia or osteoporosis. Treatment with omalizumab 300 mg every 4 weeks was initiated and immunotherapy restarted for mixed vespids and honeybee 2 weeks after the second injection of omalizumab. The patient tolerated omalizumab and immunotherapy without complications and reached maintenance doses. Omalizumab was discontinued after 6 months of maintenance immunotherapy. The patient has been maintained on immunotherapy without omalizumab for 24 months and has not presented any further anaphylactic events. He has been restung in the field once with associated mild flushing and dizziness responding to oral antihistamines, but no changes in vital signs and he did not require epinephrine.
ELEVATED TRYPTASE LEVEL AS A RISK FACTOR FOR HYMENOPTERA ANAPHYLAXIS Tryptase is the major protease produced by mast cells. It is produced in a protryptase form and cleaved to form mature and enzymatically active tryptase. Mature tryptase is stored in mast cell granules, whereas protryptase is constitutively secreted. Levels of mature (and total) tryptase in serum peak in about 1 hour after a systemic allergic reaction and return to baseline after 4 hours. Elevated baseline tryptase levels raise suspicion for states of increased mast cell burden such as mastocytosis.1 The prevalence of anaphylaxis to hymenoptera stings appears to be around 3% in the adult US population.2 The level of specific IgE detectable by blood or skin testing does not predict the severity of symptoms of the reaction.3 Because tryptase level has been elevated during severe hymenoptera reactions and at baseline in some of the patients, an associated mast cell disorder that could explain the severity and pattern of anaphylaxis has been recently investigated. Mastocytosis is a disorder characterized by the abnormal proliferation and accumulation of clonal mast cells in tissues, harboring the KIT D816V mutation and showing aberrant CD25 expression, generally accompanied by elevated baseline tryptase levels.4 Classification of mastocytosis recognizes ISM as the most common form, which can present with tryptase levels below 20 ng/mL and in the absence of skin lesions.5 Ludolph-Hauser et al6 reported that patients with elevated baseline tryptase levels of greater than 13.5 ng/mL, and
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hence an increased burden of total body mast cells, were more likely to experience severe reactions than did those with normal tryptase levels. Almost all patients with elevated tryptase levels in that study were found to have skin manifestations of mastocytosis (urticaria pigmentosa or telangiectasia macularis eruptiva perstans) on careful inspection of the skin. Akin et al7 and Sonneck et al8 reported 2 patients with a history of hymenoptera anaphylaxis who had normal tryptase levels and no cutaneous findings of mastocytosis but had abnormal clonal mast cells expressing the aberrant surface marker CD25 and carrying the KIT D816V mutation. Interestingly, these patients did not meet the full criteria to be diagnosed with systemic mastocytosis, and therefore were termed to have “monoclonal mast cell activation syndrome” (MMAS).7,8 A large multicenter European study aiming to determine the factors associated with hymenoptera reaction severity examined 962 patients who had systemic reactions.9 Elevated baseline tryptase levels, along with angiotensin-converting enzyme inhibitor therapy, male sex, vespid sting, and a history of milder reactions, were identified as determinants of the severity of reactions. Systemic reactions to honeybees are also recognized to be a risk factor.3 Bonadonna et al10 reported the largest single-center series to evaluate clonal mast cells in hymenoptera anaphylaxis. In this series of 379 patients, 11.6% had elevated tryptase levels, defined as greater than 11.4 ng/mL. These patients were evaluated with bone marrow biopsies to look for evidence of mast cell disease; 65% had evidence of either mastocytosis or MMAS. Interestingly, when a cohort of 329 patients with systemic mastocytosis was analyzed for the presence of venom anaphylaxis, levels of tryptase above the normal range and up to 28 ng/mL were associated with increased risk but higher levels were not associated with increased risk.11 Elevated baseline tryptase levels have also been recognized as a risk factor for systemic reactions during VIT.12 Although the patient presented here was late by 2 weeks for his maintenance immunotherapy injection, reactions can occur at any time during the buildup phase or maintenance in patients with mastocytosis.13 In summary, the cumulative experience suggests that elevated baseline tryptase levels and the presence of clonal mast cell disease (mastocytosis or MMAS) are strong risk factors determining the severity of hymenoptera reactions. Patients with elevated tryptase levels may or may not have skin lesions of mastocytosis.14 The bone marrow biopsy may show characteristic mast cell infiltrates of systemic mastocytosis or more limited involvement in the form of MMAS.15
Diagnosis of mastocytosis Mastocytosis is a clonal neoplastic disorder of mast cells and their hematopoietic progenitors that can be broadly categorized into cutaneous and systemic variants. By definition, patients with cutaneous mastocytosis have pathologic mast cell collections limited to the skin, whereas patients with systemic mastocytosis have bone marrow or other extracutaneous involvement proven by biopsy, with or without skin lesions.16 Cutaneous mastocytosis is the most common diagnosis in infants and children,17 whereas systemic mastocytosis is generally found in patients diagnosed as an adult. Systemic mastocytosis can be further subdivided into 4 variants on the basis of the presence or absence of tissue dysfunction and other hematologic disorders (Table I).4,18 The most common category of systemic mastocytosis is ISM, which is associated with a survival rate comparable
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FIGURE 1. A, Bone marrow biopsy showing a small perivascular aggregate of mast cells with ovoid to spindle-shaped nuclei and abundant pale cytoplasm (H&E). B, Immunohistochemistry for KIT (CD117) is positive in the aggregate of mast cells and also highlights scattered single spindle-shaped mast cells. C, The mast cells show aberrant membranous staining for CD25 (all images original magnification 400). H&E, Hematoxylin and eosin.
TABLE I. Classification of mastocytosis4 Cutaneous mastocytosis Systemic mastocytosis ISM Systemic mastocytosis associated with a hematologic disorder Aggressive systemic mastocytosis Mast cell leukemia Mast cell sarcoma Extracutaneous mastocytosis
TABLE II. Diagnostic criteria of systemic mastocytosis4: The major and at least 1 minor, or 3 minor criteria are needed Major Multifocal mast cell aggregates (>15 mast cells per aggregate) in an extracutaneous tissue (often bone marrow) biopsy Minor Abnormal mast cell morphology (spindle-shaped, hypogranulated) Aberrant CD2 or CD25 expression by mast cells Codon 816 KIT mutation in blood or lesional tissue Baseline tryptase level >20 ng/mL (not valid in patients with other hematologic disorders)
to that of the general population19 and episodic symptoms caused by inappropriate mast cell activation (ISMSY). Complications include osteopenia and osteoporosis, bone fractures,20 and anaphylaxis,21 but IgE-mediated drug or food allergies are not increased.22 Advanced forms of mastocytosis such as aggressive systemic mastocytosis are associated with bone marrow, liver, or gastrointestinal dysfunction, or the presence of another (nonemast cell) hematologic disease, usually of myeloid origin (myelodysplastic syndrome or myeloproliferative disorder).23 These patients may not have skin lesions of urticaria pigmentosa but present with much higher tryptase levels (usually much greater than 100 ng/mL). Progression from ISM to advanced forms is rare but may occur in less than 5% of the
patients.19 This patient did not present with any organomegaly or peripheral blood or bone marrow findings suggestive of an aggressive mastocytosis. The diagnosis of systemic mastocytosis requires a tissue biopsy and fulfillment of World Health Organization criteria (Table II).4 The recommended source of tissue is bone marrow because it is nearly always involved in systemic mastocytosis.16 KIT mutations and aberrant CD25 expression are consistent markers of mast cell clonality. Sometimes, 1 or 2 of these markers can be found without fulfilling the remainder of the diagnostic criteria, leading to the diagnosis of MMAS.18 CD25 expression can be measured by using flow cytometry or immunohistochemistry. In patients with low mast cell burdens and near-normal tryptase levels, mast cell flow cytometry requires significant expertise to detect low numbers of abnormal mast cells24; immunohistochemistry of serial bone marrow sections stained for tryptase, KIT (CD117), and CD25 should be considered as an alternative.25 The latter can also be applied to formalin-fixed paraffin-embedded archival biopsy specimens. Mast cells in mastocytosis and MMAS have a predilection to aggregate around blood vessels, and often have atypical spindle-shaped cytomorphology. It should be noted that elevation in tryptase level alone is not sufficient to diagnose mastocytosis in the absence of other World Health Organization criteria. Tryptase level elevations can be seen idiopathically and in patients with other disorders including hematologic disorders, and a multisystem approach to the patient with an elevated tryptase level is necessary if no evidence of mastocytosis is found.26 The most common mutation in mastocytosis in KIT D816V, which is found in more than 80% of all adults with systemic mastocytosis27,28 and approximately 40% of children in lesional tissue.29 This is a somatic mutation and is therefore often difficult to detect in blood samples, which contain very few mast cells. Therefore, mutational analysis of a bone marrow aspirate or skin biopsy specimen is more likely to yield a positive result as compared with peripheral blood. More recently developed highly sensitive assays can detect an allelic burden as low as 0.03%; peripheral blood analysis should still be
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FIGURE 2. Illustration of mast cell defects that may collectively lead to increased risk for anaphylaxis in response to hymenoptera venom in patients with clonal mast cell disease. LTC4, leukotriene C4; PGD2, prostaglandin D2.
considered as a screening test because it is useful if a positive result is found.30 D816V is a gain-of-function mutation in KIT that encodes a receptor tyrosine kinase. Under physiologic circumstances, wild-type KIT dimerizes after being cross-linked by its ligand stem cell factor. D816V-mutated KIT is constitutively autophosphorylated and sends strong signals to prevent mast cell apoptosis and drive mast cell differentiation and proliferation.28 The role of the KIT D816V mutation in mast cell activation is less clear. Although wild-type KIT has been shown to augment IgE-dependent mast cell degranulation,31 experimental evidence for the effect of D816V-mutated KIT on anaphylactic mast cell degranulation has been lacking.
MECHANISMS OF HYMENOPTERA ANAPHYLAXIS IN MASTOCYTOSIS Hymenoptera anaphylaxis may be the presenting symptom of mastocytosis in an otherwise healthy individual. A considerable number of such patients have only mildly elevated tryptase levels and lack skin findings of mastocytosis; they would not have known they had mastocytosis if they were not stung. The bone marrow may contain an only subtle mast cell infiltrate that may be overlooked if appropriate stains were not used or if the biopsy was a suboptimal specimen. The prevalence of anaphylaxis in patients with mastocytosis is approximately 30%.21,32 The presenting symptoms of anaphylaxis in this population include cardiovascular signs and symptoms such as flushing, hypotension, and near-syncopal or syncopal episodes, whereas urticaria and angioedema are rare.33 Therefore, mastocytosis should be suspected in patients whose presenting symptom was hypotension after a hymenoptera sting. The precise mechanism of increased susceptibility to hymenoptera venom anaphylaxis in mastocytosis has not been elucidated. Potential explanations include the following: (1) Increased number of mast cells amplifying the severity of the reaction
resulting from higher mast cell mediator release, (2) perivascular location of the mast cells providing direct access to the intravascular compartment, (3) D816V-mutant KIT amplifying the IgEmediated reaction, and (4) additive direct (noneIgE-mediated) mast celleactivating properties of the hymenoptera venom, including phospholipase A2 (Figure 2).
IMPLICATIONS FOR DIAGNOSIS AND THERAPY In the workup of patients with a systemic reaction to hymenoptera, a baseline tryptase level should be checked in all patients. In those with elevated tryptase levels (>11.5 ng/mL), further workup with bone marrow biopsy should be considered. It should be noted that a subset of patients with normal tryptase levels (usually in the range of 5-11.4 ng/mL) may still have evidence of clonal mast cell disease,34 and, therefore, patients presenting with hypotensive syncope after the sting (rather than urticaria or angioedema) can also be considered for referral for a bone marrow biopsy. A mutational analysis of the c-kit gene in peripheral blood can be checked first in this population, and if positive, would provide further impetus to proceed with bone marrow biopsy. These recommendations are based on the work discussed above and the authors’ own experience. In most patients with clonal mast cell disease and hymenoptera anaphylaxis, evidence of allergen-specific IgE can be found by either skin- or venom-specific IgE testing. Measured total and specific IgE levels in serum may be lower in patients with mastocytosis (presumably due to the adsorption of IgE to the surface of the expanded mast cell population) and show an inverse correlation with serum tryptase level.7 We would recommend starting with serum specific IgE levels in this population because some of these patients are on daily H1 antihistamines for symptoms of mastocytosis. This would also reduce the small risk of serious reactions during skin testing. Skin testing can then be considered for venoms that yield
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negative blood test results. Patients with negative skin test results should have skin testing repeated at least 6 weeks after the negative test results or a severe allergic reaction.3 If evidence for IgE-mediated sensitization is found, we would recommend starting VIT to venoms for which IgEmediated sensitization is detectable by skin or blood testing.35 VIT is recommended indefinitely in patients with mastocytosis and hymenoptera allergy because mastocytosis is a chronic disorder with no curative options, and systemic reactions and sting-related fatalities have been reported in patients who discontinued immunotherapy.36 Patients with mastocytosis are more likely to experience systemic reactions to immunotherapy, especially with ultrarush schedules.13 Although the lateness of the treatment in our patient may appear as a contributor to the reaction, experience has shown that anaphylactic reactions to VIT in patients with mastocytosis are somewhat random and can occur for no apparent reason. VIT should not necessarily be discontinued after a systemic reaction; adjustment of the dose and regimen is usually attempted. Premedication with H1 antihistamines and antileukotriene drugs and avoiding exercise on the day of immunotherapy should be considered for all patients. Omalizumab has been successfully used in conjunction with VIT in patients who could not previously tolerate VIT alone.37 The largest series of patients with ISM and hymenoptera allergy who underwent VIT includes an Italian and Spanish population of 84 patients reported by Bonadonna et al35 in 2013. The study consisted of 70 men and 14 women with bone marrow biopsyeproven systemic mastocytosis and a mean age of 52 years. Eighty-one percent of the patients initially presented with anaphylaxis after hymenoptera sting, and 63% had loss of consciousness at the time of the reaction. Patients were reactive to honeybee, polistes (including yellow jacket), and vespula (including wasps) and had specific IgE through skin testing and/or blood CAP testing. Patients were treated with classical VIT or modified rush and presented only 10 reactions before reaching maintenance, which did not require epinephrine or hospitalization. The patients were maintained on monthly injections every 4 weeks and then every 3 months continuously. Fifty-one patients had 95 stings after the initiation of immunotherapy, and 43 patients (86%) were fully protected. Of the 7 reactive patients, none died; they required epinephrine injections but no hospitalization. An increase from 100 mg to 200 mg of venom was recommended for the reactive patients, but no outcomes were provided. It is of interest to recognize that up to 25% of the patients with mastocytosis with hymenoptera venom allergy are not fully protected by conventional VIT.13 This has raised the question as to whether increasing maintenance doses beyond the recommended guidelines may afford increased protection against anaphylaxis when patients are stung in the field.38 Recently, Kohler et al39 have described the molecular components of bee venom and identified additional major allergens, revealing sensitizations to allergens that have been reported to be absent or underrepresented in commercial immunotherapy preparations. It may therefore be indicated in some patients with mastocytosis and severe anaphylaxis to hymenoptera who react during VIT to investigate the molecular components of their venom IgE. Providing specific immunotherapy to these components would be expected to protect them against life-threatening episodes of anaphylaxis when stung in the field.
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SUMMARY Patients presenting with anaphylaxis during hymenoptera stings are at high risk for clonal mast cell disorders including MMAS and systemic mastocytosis. These disorders are characterized by CD25 aberrant expression in mast cells and KIT mutations, D816V being the most common. Tryptase levels should be checked in all patients with a history of a systemic reaction to hymenoptera. Although males predominate in the reported studies, females can also be affected. Skin testing and specific IgE are recommended to unravel the culprit hymenoptera, and immunotherapy for life is the standard of care. For patients with high sensitivity, omalizumab may be of used while reaching maintenance, and investigation of specific venom components may be indicated to provide specific allergens for immunotherapy. Deaths have been reported in patients with systemic mastocytosis who discontinued immunotherapy and were stung in the field. Increased protection against anaphylaxis may result from the addition of specific components to commercial VIT vaccines. The role of KIT mutations in patients with hymenoptera anaphylaxis and clonal mast cell disorders has not been defined, and tyrosine kinase inhibitors are not recommended as therapy at the present time. REFERENCES 1. Schwartz LB, Sakai K, Bradford TR, Ren S, Zweiman B, Worobec AS, et al. The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis. J Clin Invest 1995;96:2702-10. 2. Golden DB, Marsh DG, Freidhoff LR, Kwiterovich KA, Addison B, KageySobotka A, et al. Natural history of Hymenoptera venom sensitivity in adults. J Allergy Clin Immunol 1997;100:760-6. 3. Golden DB, Moffitt J, Nicklas RA, Freeman T, Graft DF, Reisman RE, et al. Stinging insect hypersensitivity: a practice parameter update 2011. J Allergy Clin Immunol 2011;127:852-4. e1-23. 4. Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res 2001;25:603-25. 5. Valent P, Aberer E, Beham-Schmid C, Fellinger C, Fuchs W, Gleixner KV, et al. Guidelines and diagnostic algorithm for patients with suspected systemic mastocytosis: a proposal of the Austrian competence network (AUCNM). Am J Blood Res 2013;3:174-80. 6. Ludolph-Hauser D, Rueff F, Fries C, Schopf P, Przybilla B. Constitutively raised serum concentrations of mast-cell tryptase and severe anaphylactic reactions to Hymenoptera stings. Lancet 2001;357:361-2. 7. Akin C, Scott LM, Kocabas CN, Kushnir-Sukhov N, Brittain E, Noel P, et al. Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis. Blood 2007;110: 2331-3. 8. Sonneck K, Florian S, Mullauer L, Wimazal F, Fodinger M, Sperr WR, et al. Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: monoclonal mast cell activation syndrome. Int Arch Allergy Immunol 2006;142:158-64. 9. Rueff F, Przybilla B, Bilo MB, Muller U, Scheipl F, Aberer W, et al. Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: importance of baseline serum tryptase—a study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity. J Allergy Clin Immunol 2009;124:1047-54. 10. Bonadonna P, Perbellini O, Passalacqua G, Caruso B, Colarossi S, Dal Fior D, et al. Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels. J Allergy Clin Immunol 2009;123:680-6. 11. van Anrooij B, van der Veer E, de Monchy JG, van der Heide S, KluinNelemans JC, van Voorst Vader PC, et al. Higher mast cell load decreases the risk of Hymenoptera venom-induced anaphylaxis in patients with mastocytosis. J Allergy Clin Immunol 2013;132:125-30. 12. Rueff F, Przybilla B, Bilo MB, Muller U, Scheipl F, Aberer W, et al. Predictors of side effects during the buildup phase of venom immunotherapy for Hymenoptera venom allergy: the importance of baseline serum tryptase. J Allergy Clin Immunol 2010;126:105-111.e5.
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13. Gonzalez de Olano D, Alvarez-Twose I, Esteban-Lopez MI, Sanchez-Munoz L, de Durana MD, Vega A, et al. Safety and effectiveness of immunotherapy in patients with indolent systemic mastocytosis presenting with Hymenoptera venom anaphylaxis. J Allergy Clin Immunol 2008;121:519-26. 14. Alvarez-Twose I, Zanotti R, Gonzalez-de-Olano D, Bonadonna P, Vega A, Matito A, et al. Nonaggressive systemic mastocytosis (SM) without skin lesions associated with insect-induced anaphylaxis shows unique features versus other indolent SM. J Allergy Clin Immunol 2014;133:520-8. 15. Picard M, Giavina-Bianchi P, Mezzano V, Castells M. Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clin Ther 2013;35:548-62. 16. Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest 2007;37:435-53. 17. Castells M, Metcalfe DD, Escribano L. Diagnosis and treatment of cutaneous mastocytosis in children: practical recommendations. Am J Clin Dermatol 2011; 12:259-70. 18. Akin C, Valent P. Diagnostic criteria and classification of mastocytosis in 2014. Immunol Allergy Clin North Am 2014;34:207-18. 19. Escribano L, Alvarez-Twose I, Sanchez-Munoz L, Garcia-Montero A, Nunez R, Almeida J, et al. Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish Network on Mastocytosis in a series of 145 patients. J Allergy Clin Immunol 2009;124:514-21. 20. van der Veer E, van der Goot W, de Monchy JG, Kluin-Nelemans HC, van Doormaal JJ. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy 2012;67:431-8. 21. Brockow K, Jofer C, Behrendt H, Ring J. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy 2008;63:226-32. 22. Bonadonna P, Zanotti R, Pagani M, Caruso B, Perbellini O, Colarossi S, et al. How much specific is the association between hymenoptera venom allergy and mastocytosis? Allergy 2009;64:1379-82. 23. Valent P, Sperr WR, Akin C. How I treat patients with advanced systemic mastocytosis. Blood 2010;116:5812-7. 24. Escribano L, Diaz-Agustin B, Lopez A, Nunez Lopez R, Garcia-Montero A, Almeida J, et al. Immunophenotypic analysis of mast cells in mastocytosis: when and how to do it. Proposals of the Spanish Network on Mastocytosis (REMA). Cytometry B Clin Cytom 2004;58:1-8. 25. Sotlar K, Horny HP, Simonitsch I, Krokowski M, Aichberger KJ, Mayerhofer M, et al. CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens. Am J Surg Pathol 2004;28:1319-25. 26. Schwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunol Allergy Clin North Am 2006;26:451-63.
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27. Arock M, Sotlar K, Akin C, Broesby-Olsen S, Hoermann G, Escribano L, et al. KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis. Leukemia. 2015. Epub February 2, 2015. 28. Akin C, Metcalfe DD. The biology of Kit in disease and the application of pharmacogenetics. J Allergy Clin Immunol 2004;114:13-9. 29. Bodemer C, Hermine O, Palmerini F, Yang Y, Grandpeix-Guyodo C, Leventhal PS, et al. Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations. J Invest Dermatol 2010;130: 804-15. 30. Kristensen T, Vestergaard H, Moller MB. Improved detection of the KIT D816V mutation in patients with systemic mastocytosis using a quantitative and highly sensitive real-time qPCR assay. J Mol Diagn 2011;13:180-8. 31. Hundley TR, Gilfillan AM, Tkaczyk C, Andrade MV, Metcalfe DD, Beaven MA. Kit and FcepsilonRI mediate unique and convergent signals for release of inflammatory mediators from human mast cells. Blood 2004;104: 2410-7. 32. Gonzalez de Olano D, de la Hoz Caballer B, Nunez Lopez R, Sanchez Munoz L, Cuevas Agustin M, Dieguez MC, et al. Prevalence of allergy and anaphylactic symptoms in 210 adult and pediatric patients with mastocytosis in Spain: a study of the Spanish network on mastocytosis (REMA). Clin Exp Allergy 2007;37: 1547-55. 33. Alvarez-Twose I, Gonzalez de Olano D, Sanchez-Munoz L, Matito A, EstebanLopez MI, Vega A, et al. Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms. J Allergy Clin Immunol 2010;125:1269-1278.e2. 34. Zanotti R, Lombardo C, Passalacqua G, Caimmi C, Bonifacio M, De Matteis G, et al. Clonal mast cell disorders in patients with severe Hymenoptera venom allergy and normal serum tryptase levels. The Journal of Allergy and Clinical Immunology. 2015. Epub January 22, 2015. 35. Bonadonna P, Gonzalez-de-Olano D, Zanotti R, Riccio A, De Ferrari L, Lombardo C, et al. Venom immunotherapy in patients with clonal mast cell disorders: efficacy, safety, and practical considerations. J Allergy Clin Immunol Pract 2013;1:474-8. 36. Oude Elberink JN, de Monchy JG, Kors JW, van Doormaal JJ, Dubois AE. Fatal anaphylaxis after a yellow jacket sting, despite venom immunotherapy, in two patients with mastocytosis. J Allergy Clin Immunol 1997;99:153-4. 37. Sokol KC, Ghazi A, Kelly BC, Grant JA. Omalizumab as a desensitizing agent and treatment in mastocytosis: a review of the literature and case report. J Allergy Clin Immunol Pract 2014;2:266-70. 38. Rueff F, Wenderoth A, Przybilla B. Patients still reacting to a sting challenge while receiving conventional Hymenoptera venom immunotherapy are protected by increased venom doses. J Allergy Clin Immunol 2001;108:1027-32. 39. Kohler J, Blank S, Muller S, Bantleon F, Frick M, Huss-Marp J, et al. Component resolution reveals additional major allergens in patients with honeybee venom allergy. J Allergy Clin Immunol 2014;133:1383-9. 1389.e1-6.
Anaphylaxis After Hymenoptera Sting: Is It Venom Allergy, a Clonal Disorder, or Both? Mariana C. Castells, MD, PhD, Jason L. Hornick, MD, PhD, and Cem Akin, MD, PhD A 47-year-old man presented with loss of consciousness 5 minutes after being stung by a yellow jacket in his backyard. Epinephrine and fluids were required for resuscitation. Allergy evaluation revealed specific IgE to yellow jacket and honeybee, and the patient was started on venom immunotherapy. He had systemic reactions during buildup and a severe anaphylactic episode requiring 3 doses of intramuscular epinephrine at maintenance doses. Immunotherapy was discontinued. Serum tryptase level after 1 such episode was 29 ng/mL, with a baseline level of 25 ng/mL 4 weeks later. The physical examination was unremarkable including no skin lesions of cutaneous mastocytosis. Because of elevated baseline tryptase level, a bone marrow biopsy was performed, which revealed multifocal dense infiltrates of mast cells. A diagnosis of systemic mastocytosis was made. The patient was treated with omalizumab and was able to tolerate immunotherapy and is currently maintained on lifelong immunotherapy. He was restung in the field and has not had anaphylaxis. Ó 2015 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2015;3:350-5) Key words: Mastocytosis
Mast
cells;
Hymenoptera;
c-kit
anaphylaxis. A bone marrow biopsy and aspiration should be considered for those with elevated baseline tryptase levels. Complications of systemic mastocytosis include osteopenia and osteoporosis, which can lead to bone fractures and can be prevented with early treatment. Progression to aggressive mastocytosis or an associated hematological malignancy can occur in a small subset of patients with systemic mastocytosis but has not been documented in patients presenting initially with hymenoptera anaphylaxis. A small number of patients can also have severe anaphylactic reactions to certain drugs (including nonsteroidal anti-inflammatory drugs, opioids, vancomycin, and muscle relaxants) and contrast dyes. Premedication regimens similar to those used in prophylaxis of contrast dye allergy have been proposed before medical procedures involving general anesthesia, although the efficacy of these regimens has not been systemically evaluated. Upper gastrointestinal irritation due to gastric acid hypersecretion is another common complication and can be prevented by the use of H2 antihistamines and proton pump inhibitors.
mutations;
The presentation, diagnosis, and molecular features of a subset of indolent systemic mastocytosis (ISM) associated with hymenoptera anaphylaxis are reviewed, and the approach to management and treatment is discussed. Patients with anaphylactic reactions to hymenoptera venom presenting with hypotension are at an increased risk for having systemic mastocytosis as the underlying diagnosis, modifying the severity of the presentation. A baseline serum tryptase level is recommended as a screening test for all patients with hymenoptera
Mastocytosis Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass Conflicts of interest: M. C. Castells is on the American Academy of Allergy, Asthma & Immunology Board; has received consultancy fees from Sanofi; is employed by Brigham and Women’s Hospital; has received research support from Ovations for the Cure; has received lecture fees from the Kansas Allergy Society; and receives royalties from UpToDate. C. Akin has received consultancy fees from Novartis, Patara Pharma, and Blueprint Medicines; is employed by Brigham and Women’s Hospital; and has a patent through the National Institutes of Health (LAD2 cell line). J. L. Hornick declares that he has no relevant conflicts of interest. Received for publication January 26, 2015; revised March 28, 2015; accepted for publication March 30, 2015. Available online April 7, 2015. Corresponding author: Mariana C. Castells, MD, PhD, Harvard Medical School, Brigham and Women’s Hospital, 1 Jimmy Fund Way, Smith Bldg, Rm 626D, Boston, MA 02115. E-mail: [email protected]. 2213-2198 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2015.03.015
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CLINICAL PRESENTATION A 47-year-old man working in his backyard was stung by a yellow jacket. He felt weak and dizzy with tunnel vision and lost consciousness within 5 minutes. Epinephrine was injected intramuscularly in the field, and he was brought to the emergency room. He received fluids, antihistamines, and glucocorticosteroids, and he recovered without sequelae. Evaluation by skin testing 6 weeks later was negative for all hymenoptera venoms, possibly due to the anergic period following anaphylaxis, but specific IgE was positive for yellow jacket (class II) and honeybee (class I). He was started on venom immunotherapy (VIT) with mixed vespids and honeybee at an outside allergy clinic. He had mild to moderate systemic reactions while receiving buildup doses, requiring several epinephrine injections, but was able to reach maintenance and started a program of 300 mg of mixed vespids and 100 mg of honeybee every 4 weeks. At the second injection of maintenance, he was 2 weeks late (6 weeks since his last injection) and had immediate tunnel vision, hypotension, oxygen desaturation, and loss of consciousness and required 3 doses of intramuscular epinephrine for resuscitation. A tryptase level (the exact timing was unclear but within 24 hours of the reaction) was found to be elevated at 29 ng/mL. Immunotherapy was discontinued, and the patient care was transferred to the Brigham and Women’s Hospital Mastocytosis Center. A tryptase baseline repeat level 4 weeks later was 25 ng/mL. The patient had a full-body skin examination that ruled out urticaria pigmentosa, mastocytoma, or other forms of cutaneous mastocytosis that could explain the elevation in the tryptase level. He had no organomegaly or lymphadenopathy. The patient had a history of allergic rhinitis
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Abbreviations used MMAS- Monoclonal mast cell activation syndrome VIT- Venom immunotherapy
and mild asthma and used over-the-counter antihistamines and bronchodilators intermittently. His review of systems was positive for frequent episodes of flushing associated with palpitations, abdominal bloating and pain, and intermittent diarrhea for the last 2 to 3 years. He complained of generalized bone pain and mild depression and anxiety. He denied food allergies and had not used oral steroids or been hospitalized for his asthma. A bone marrow biopsy was performed because of the baseline elevated tryptase level and showed small perivascular aggregates of mast cells including atypical spindle-shaped forms, which were positive for CD25 (Figure 1). The patient received a diagnosis of ISM. His bone marrow did not show evidence of myelodysplastic or myeloproliferative disorders, and his peripheral blood cell counts were within normal range without eosinophilia. His liver enzymes and metabolic panel were normal, and a bone densitometry was normal without evidence of osteopenia or osteoporosis. Treatment with omalizumab 300 mg every 4 weeks was initiated and immunotherapy restarted for mixed vespids and honeybee 2 weeks after the second injection of omalizumab. The patient tolerated omalizumab and immunotherapy without complications and reached maintenance doses. Omalizumab was discontinued after 6 months of maintenance immunotherapy. The patient has been maintained on immunotherapy without omalizumab for 24 months and has not presented any further anaphylactic events. He has been restung in the field once with associated mild flushing and dizziness responding to oral antihistamines, but no changes in vital signs and he did not require epinephrine.
ELEVATED TRYPTASE LEVEL AS A RISK FACTOR FOR HYMENOPTERA ANAPHYLAXIS Tryptase is the major protease produced by mast cells. It is produced in a protryptase form and cleaved to form mature and enzymatically active tryptase. Mature tryptase is stored in mast cell granules, whereas protryptase is constitutively secreted. Levels of mature (and total) tryptase in serum peak in about 1 hour after a systemic allergic reaction and return to baseline after 4 hours. Elevated baseline tryptase levels raise suspicion for states of increased mast cell burden such as mastocytosis.1 The prevalence of anaphylaxis to hymenoptera stings appears to be around 3% in the adult US population.2 The level of specific IgE detectable by blood or skin testing does not predict the severity of symptoms of the reaction.3 Because tryptase level has been elevated during severe hymenoptera reactions and at baseline in some of the patients, an associated mast cell disorder that could explain the severity and pattern of anaphylaxis has been recently investigated. Mastocytosis is a disorder characterized by the abnormal proliferation and accumulation of clonal mast cells in tissues, harboring the KIT D816V mutation and showing aberrant CD25 expression, generally accompanied by elevated baseline tryptase levels.4 Classification of mastocytosis recognizes ISM as the most common form, which can present with tryptase levels below 20 ng/mL and in the absence of skin lesions.5 Ludolph-Hauser et al6 reported that patients with elevated baseline tryptase levels of greater than 13.5 ng/mL, and
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hence an increased burden of total body mast cells, were more likely to experience severe reactions than did those with normal tryptase levels. Almost all patients with elevated tryptase levels in that study were found to have skin manifestations of mastocytosis (urticaria pigmentosa or telangiectasia macularis eruptiva perstans) on careful inspection of the skin. Akin et al7 and Sonneck et al8 reported 2 patients with a history of hymenoptera anaphylaxis who had normal tryptase levels and no cutaneous findings of mastocytosis but had abnormal clonal mast cells expressing the aberrant surface marker CD25 and carrying the KIT D816V mutation. Interestingly, these patients did not meet the full criteria to be diagnosed with systemic mastocytosis, and therefore were termed to have “monoclonal mast cell activation syndrome” (MMAS).7,8 A large multicenter European study aiming to determine the factors associated with hymenoptera reaction severity examined 962 patients who had systemic reactions.9 Elevated baseline tryptase levels, along with angiotensin-converting enzyme inhibitor therapy, male sex, vespid sting, and a history of milder reactions, were identified as determinants of the severity of reactions. Systemic reactions to honeybees are also recognized to be a risk factor.3 Bonadonna et al10 reported the largest single-center series to evaluate clonal mast cells in hymenoptera anaphylaxis. In this series of 379 patients, 11.6% had elevated tryptase levels, defined as greater than 11.4 ng/mL. These patients were evaluated with bone marrow biopsies to look for evidence of mast cell disease; 65% had evidence of either mastocytosis or MMAS. Interestingly, when a cohort of 329 patients with systemic mastocytosis was analyzed for the presence of venom anaphylaxis, levels of tryptase above the normal range and up to 28 ng/mL were associated with increased risk but higher levels were not associated with increased risk.11 Elevated baseline tryptase levels have also been recognized as a risk factor for systemic reactions during VIT.12 Although the patient presented here was late by 2 weeks for his maintenance immunotherapy injection, reactions can occur at any time during the buildup phase or maintenance in patients with mastocytosis.13 In summary, the cumulative experience suggests that elevated baseline tryptase levels and the presence of clonal mast cell disease (mastocytosis or MMAS) are strong risk factors determining the severity of hymenoptera reactions. Patients with elevated tryptase levels may or may not have skin lesions of mastocytosis.14 The bone marrow biopsy may show characteristic mast cell infiltrates of systemic mastocytosis or more limited involvement in the form of MMAS.15
Diagnosis of mastocytosis Mastocytosis is a clonal neoplastic disorder of mast cells and their hematopoietic progenitors that can be broadly categorized into cutaneous and systemic variants. By definition, patients with cutaneous mastocytosis have pathologic mast cell collections limited to the skin, whereas patients with systemic mastocytosis have bone marrow or other extracutaneous involvement proven by biopsy, with or without skin lesions.16 Cutaneous mastocytosis is the most common diagnosis in infants and children,17 whereas systemic mastocytosis is generally found in patients diagnosed as an adult. Systemic mastocytosis can be further subdivided into 4 variants on the basis of the presence or absence of tissue dysfunction and other hematologic disorders (Table I).4,18 The most common category of systemic mastocytosis is ISM, which is associated with a survival rate comparable
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FIGURE 1. A, Bone marrow biopsy showing a small perivascular aggregate of mast cells with ovoid to spindle-shaped nuclei and abundant pale cytoplasm (H&E). B, Immunohistochemistry for KIT (CD117) is positive in the aggregate of mast cells and also highlights scattered single spindle-shaped mast cells. C, The mast cells show aberrant membranous staining for CD25 (all images original magnification 400). H&E, Hematoxylin and eosin.
TABLE I. Classification of mastocytosis4 Cutaneous mastocytosis Systemic mastocytosis ISM Systemic mastocytosis associated with a hematologic disorder Aggressive systemic mastocytosis Mast cell leukemia Mast cell sarcoma Extracutaneous mastocytosis
TABLE II. Diagnostic criteria of systemic mastocytosis4: The major and at least 1 minor, or 3 minor criteria are needed Major Multifocal mast cell aggregates (>15 mast cells per aggregate) in an extracutaneous tissue (often bone marrow) biopsy Minor Abnormal mast cell morphology (spindle-shaped, hypogranulated) Aberrant CD2 or CD25 expression by mast cells Codon 816 KIT mutation in blood or lesional tissue Baseline tryptase level >20 ng/mL (not valid in patients with other hematologic disorders)
to that of the general population19 and episodic symptoms caused by inappropriate mast cell activation (ISMSY). Complications include osteopenia and osteoporosis, bone fractures,20 and anaphylaxis,21 but IgE-mediated drug or food allergies are not increased.22 Advanced forms of mastocytosis such as aggressive systemic mastocytosis are associated with bone marrow, liver, or gastrointestinal dysfunction, or the presence of another (nonemast cell) hematologic disease, usually of myeloid origin (myelodysplastic syndrome or myeloproliferative disorder).23 These patients may not have skin lesions of urticaria pigmentosa but present with much higher tryptase levels (usually much greater than 100 ng/mL). Progression from ISM to advanced forms is rare but may occur in less than 5% of the
patients.19 This patient did not present with any organomegaly or peripheral blood or bone marrow findings suggestive of an aggressive mastocytosis. The diagnosis of systemic mastocytosis requires a tissue biopsy and fulfillment of World Health Organization criteria (Table II).4 The recommended source of tissue is bone marrow because it is nearly always involved in systemic mastocytosis.16 KIT mutations and aberrant CD25 expression are consistent markers of mast cell clonality. Sometimes, 1 or 2 of these markers can be found without fulfilling the remainder of the diagnostic criteria, leading to the diagnosis of MMAS.18 CD25 expression can be measured by using flow cytometry or immunohistochemistry. In patients with low mast cell burdens and near-normal tryptase levels, mast cell flow cytometry requires significant expertise to detect low numbers of abnormal mast cells24; immunohistochemistry of serial bone marrow sections stained for tryptase, KIT (CD117), and CD25 should be considered as an alternative.25 The latter can also be applied to formalin-fixed paraffin-embedded archival biopsy specimens. Mast cells in mastocytosis and MMAS have a predilection to aggregate around blood vessels, and often have atypical spindle-shaped cytomorphology. It should be noted that elevation in tryptase level alone is not sufficient to diagnose mastocytosis in the absence of other World Health Organization criteria. Tryptase level elevations can be seen idiopathically and in patients with other disorders including hematologic disorders, and a multisystem approach to the patient with an elevated tryptase level is necessary if no evidence of mastocytosis is found.26 The most common mutation in mastocytosis in KIT D816V, which is found in more than 80% of all adults with systemic mastocytosis27,28 and approximately 40% of children in lesional tissue.29 This is a somatic mutation and is therefore often difficult to detect in blood samples, which contain very few mast cells. Therefore, mutational analysis of a bone marrow aspirate or skin biopsy specimen is more likely to yield a positive result as compared with peripheral blood. More recently developed highly sensitive assays can detect an allelic burden as low as 0.03%; peripheral blood analysis should still be
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FIGURE 2. Illustration of mast cell defects that may collectively lead to increased risk for anaphylaxis in response to hymenoptera venom in patients with clonal mast cell disease. LTC4, leukotriene C4; PGD2, prostaglandin D2.
considered as a screening test because it is useful if a positive result is found.30 D816V is a gain-of-function mutation in KIT that encodes a receptor tyrosine kinase. Under physiologic circumstances, wild-type KIT dimerizes after being cross-linked by its ligand stem cell factor. D816V-mutated KIT is constitutively autophosphorylated and sends strong signals to prevent mast cell apoptosis and drive mast cell differentiation and proliferation.28 The role of the KIT D816V mutation in mast cell activation is less clear. Although wild-type KIT has been shown to augment IgE-dependent mast cell degranulation,31 experimental evidence for the effect of D816V-mutated KIT on anaphylactic mast cell degranulation has been lacking.
MECHANISMS OF HYMENOPTERA ANAPHYLAXIS IN MASTOCYTOSIS Hymenoptera anaphylaxis may be the presenting symptom of mastocytosis in an otherwise healthy individual. A considerable number of such patients have only mildly elevated tryptase levels and lack skin findings of mastocytosis; they would not have known they had mastocytosis if they were not stung. The bone marrow may contain an only subtle mast cell infiltrate that may be overlooked if appropriate stains were not used or if the biopsy was a suboptimal specimen. The prevalence of anaphylaxis in patients with mastocytosis is approximately 30%.21,32 The presenting symptoms of anaphylaxis in this population include cardiovascular signs and symptoms such as flushing, hypotension, and near-syncopal or syncopal episodes, whereas urticaria and angioedema are rare.33 Therefore, mastocytosis should be suspected in patients whose presenting symptom was hypotension after a hymenoptera sting. The precise mechanism of increased susceptibility to hymenoptera venom anaphylaxis in mastocytosis has not been elucidated. Potential explanations include the following: (1) Increased number of mast cells amplifying the severity of the reaction
resulting from higher mast cell mediator release, (2) perivascular location of the mast cells providing direct access to the intravascular compartment, (3) D816V-mutant KIT amplifying the IgEmediated reaction, and (4) additive direct (noneIgE-mediated) mast celleactivating properties of the hymenoptera venom, including phospholipase A2 (Figure 2).
IMPLICATIONS FOR DIAGNOSIS AND THERAPY In the workup of patients with a systemic reaction to hymenoptera, a baseline tryptase level should be checked in all patients. In those with elevated tryptase levels (>11.5 ng/mL), further workup with bone marrow biopsy should be considered. It should be noted that a subset of patients with normal tryptase levels (usually in the range of 5-11.4 ng/mL) may still have evidence of clonal mast cell disease,34 and, therefore, patients presenting with hypotensive syncope after the sting (rather than urticaria or angioedema) can also be considered for referral for a bone marrow biopsy. A mutational analysis of the c-kit gene in peripheral blood can be checked first in this population, and if positive, would provide further impetus to proceed with bone marrow biopsy. These recommendations are based on the work discussed above and the authors’ own experience. In most patients with clonal mast cell disease and hymenoptera anaphylaxis, evidence of allergen-specific IgE can be found by either skin- or venom-specific IgE testing. Measured total and specific IgE levels in serum may be lower in patients with mastocytosis (presumably due to the adsorption of IgE to the surface of the expanded mast cell population) and show an inverse correlation with serum tryptase level.7 We would recommend starting with serum specific IgE levels in this population because some of these patients are on daily H1 antihistamines for symptoms of mastocytosis. This would also reduce the small risk of serious reactions during skin testing. Skin testing can then be considered for venoms that yield
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negative blood test results. Patients with negative skin test results should have skin testing repeated at least 6 weeks after the negative test results or a severe allergic reaction.3 If evidence for IgE-mediated sensitization is found, we would recommend starting VIT to venoms for which IgEmediated sensitization is detectable by skin or blood testing.35 VIT is recommended indefinitely in patients with mastocytosis and hymenoptera allergy because mastocytosis is a chronic disorder with no curative options, and systemic reactions and sting-related fatalities have been reported in patients who discontinued immunotherapy.36 Patients with mastocytosis are more likely to experience systemic reactions to immunotherapy, especially with ultrarush schedules.13 Although the lateness of the treatment in our patient may appear as a contributor to the reaction, experience has shown that anaphylactic reactions to VIT in patients with mastocytosis are somewhat random and can occur for no apparent reason. VIT should not necessarily be discontinued after a systemic reaction; adjustment of the dose and regimen is usually attempted. Premedication with H1 antihistamines and antileukotriene drugs and avoiding exercise on the day of immunotherapy should be considered for all patients. Omalizumab has been successfully used in conjunction with VIT in patients who could not previously tolerate VIT alone.37 The largest series of patients with ISM and hymenoptera allergy who underwent VIT includes an Italian and Spanish population of 84 patients reported by Bonadonna et al35 in 2013. The study consisted of 70 men and 14 women with bone marrow biopsyeproven systemic mastocytosis and a mean age of 52 years. Eighty-one percent of the patients initially presented with anaphylaxis after hymenoptera sting, and 63% had loss of consciousness at the time of the reaction. Patients were reactive to honeybee, polistes (including yellow jacket), and vespula (including wasps) and had specific IgE through skin testing and/or blood CAP testing. Patients were treated with classical VIT or modified rush and presented only 10 reactions before reaching maintenance, which did not require epinephrine or hospitalization. The patients were maintained on monthly injections every 4 weeks and then every 3 months continuously. Fifty-one patients had 95 stings after the initiation of immunotherapy, and 43 patients (86%) were fully protected. Of the 7 reactive patients, none died; they required epinephrine injections but no hospitalization. An increase from 100 mg to 200 mg of venom was recommended for the reactive patients, but no outcomes were provided. It is of interest to recognize that up to 25% of the patients with mastocytosis with hymenoptera venom allergy are not fully protected by conventional VIT.13 This has raised the question as to whether increasing maintenance doses beyond the recommended guidelines may afford increased protection against anaphylaxis when patients are stung in the field.38 Recently, Kohler et al39 have described the molecular components of bee venom and identified additional major allergens, revealing sensitizations to allergens that have been reported to be absent or underrepresented in commercial immunotherapy preparations. It may therefore be indicated in some patients with mastocytosis and severe anaphylaxis to hymenoptera who react during VIT to investigate the molecular components of their venom IgE. Providing specific immunotherapy to these components would be expected to protect them against life-threatening episodes of anaphylaxis when stung in the field.
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SUMMARY Patients presenting with anaphylaxis during hymenoptera stings are at high risk for clonal mast cell disorders including MMAS and systemic mastocytosis. These disorders are characterized by CD25 aberrant expression in mast cells and KIT mutations, D816V being the most common. Tryptase levels should be checked in all patients with a history of a systemic reaction to hymenoptera. Although males predominate in the reported studies, females can also be affected. Skin testing and specific IgE are recommended to unravel the culprit hymenoptera, and immunotherapy for life is the standard of care. For patients with high sensitivity, omalizumab may be of used while reaching maintenance, and investigation of specific venom components may be indicated to provide specific allergens for immunotherapy. Deaths have been reported in patients with systemic mastocytosis who discontinued immunotherapy and were stung in the field. Increased protection against anaphylaxis may result from the addition of specific components to commercial VIT vaccines. The role of KIT mutations in patients with hymenoptera anaphylaxis and clonal mast cell disorders has not been defined, and tyrosine kinase inhibitors are not recommended as therapy at the present time. REFERENCES 1. Schwartz LB, Sakai K, Bradford TR, Ren S, Zweiman B, Worobec AS, et al. The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis. J Clin Invest 1995;96:2702-10. 2. Golden DB, Marsh DG, Freidhoff LR, Kwiterovich KA, Addison B, KageySobotka A, et al. Natural history of Hymenoptera venom sensitivity in adults. J Allergy Clin Immunol 1997;100:760-6. 3. Golden DB, Moffitt J, Nicklas RA, Freeman T, Graft DF, Reisman RE, et al. Stinging insect hypersensitivity: a practice parameter update 2011. J Allergy Clin Immunol 2011;127:852-4. e1-23. 4. Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res 2001;25:603-25. 5. Valent P, Aberer E, Beham-Schmid C, Fellinger C, Fuchs W, Gleixner KV, et al. Guidelines and diagnostic algorithm for patients with suspected systemic mastocytosis: a proposal of the Austrian competence network (AUCNM). Am J Blood Res 2013;3:174-80. 6. Ludolph-Hauser D, Rueff F, Fries C, Schopf P, Przybilla B. Constitutively raised serum concentrations of mast-cell tryptase and severe anaphylactic reactions to Hymenoptera stings. Lancet 2001;357:361-2. 7. Akin C, Scott LM, Kocabas CN, Kushnir-Sukhov N, Brittain E, Noel P, et al. Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis. Blood 2007;110: 2331-3. 8. Sonneck K, Florian S, Mullauer L, Wimazal F, Fodinger M, Sperr WR, et al. Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: monoclonal mast cell activation syndrome. Int Arch Allergy Immunol 2006;142:158-64. 9. Rueff F, Przybilla B, Bilo MB, Muller U, Scheipl F, Aberer W, et al. Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: importance of baseline serum tryptase—a study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity. J Allergy Clin Immunol 2009;124:1047-54. 10. Bonadonna P, Perbellini O, Passalacqua G, Caruso B, Colarossi S, Dal Fior D, et al. Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels. J Allergy Clin Immunol 2009;123:680-6. 11. van Anrooij B, van der Veer E, de Monchy JG, van der Heide S, KluinNelemans JC, van Voorst Vader PC, et al. Higher mast cell load decreases the risk of Hymenoptera venom-induced anaphylaxis in patients with mastocytosis. J Allergy Clin Immunol 2013;132:125-30. 12. Rueff F, Przybilla B, Bilo MB, Muller U, Scheipl F, Aberer W, et al. Predictors of side effects during the buildup phase of venom immunotherapy for Hymenoptera venom allergy: the importance of baseline serum tryptase. J Allergy Clin Immunol 2010;126:105-111.e5.
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13. Gonzalez de Olano D, Alvarez-Twose I, Esteban-Lopez MI, Sanchez-Munoz L, de Durana MD, Vega A, et al. Safety and effectiveness of immunotherapy in patients with indolent systemic mastocytosis presenting with Hymenoptera venom anaphylaxis. J Allergy Clin Immunol 2008;121:519-26. 14. Alvarez-Twose I, Zanotti R, Gonzalez-de-Olano D, Bonadonna P, Vega A, Matito A, et al. Nonaggressive systemic mastocytosis (SM) without skin lesions associated with insect-induced anaphylaxis shows unique features versus other indolent SM. J Allergy Clin Immunol 2014;133:520-8. 15. Picard M, Giavina-Bianchi P, Mezzano V, Castells M. Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clin Ther 2013;35:548-62. 16. Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest 2007;37:435-53. 17. Castells M, Metcalfe DD, Escribano L. Diagnosis and treatment of cutaneous mastocytosis in children: practical recommendations. Am J Clin Dermatol 2011; 12:259-70. 18. Akin C, Valent P. Diagnostic criteria and classification of mastocytosis in 2014. Immunol Allergy Clin North Am 2014;34:207-18. 19. Escribano L, Alvarez-Twose I, Sanchez-Munoz L, Garcia-Montero A, Nunez R, Almeida J, et al. Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish Network on Mastocytosis in a series of 145 patients. J Allergy Clin Immunol 2009;124:514-21. 20. van der Veer E, van der Goot W, de Monchy JG, Kluin-Nelemans HC, van Doormaal JJ. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy 2012;67:431-8. 21. Brockow K, Jofer C, Behrendt H, Ring J. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy 2008;63:226-32. 22. Bonadonna P, Zanotti R, Pagani M, Caruso B, Perbellini O, Colarossi S, et al. How much specific is the association between hymenoptera venom allergy and mastocytosis? Allergy 2009;64:1379-82. 23. Valent P, Sperr WR, Akin C. How I treat patients with advanced systemic mastocytosis. Blood 2010;116:5812-7. 24. Escribano L, Diaz-Agustin B, Lopez A, Nunez Lopez R, Garcia-Montero A, Almeida J, et al. Immunophenotypic analysis of mast cells in mastocytosis: when and how to do it. Proposals of the Spanish Network on Mastocytosis (REMA). Cytometry B Clin Cytom 2004;58:1-8. 25. Sotlar K, Horny HP, Simonitsch I, Krokowski M, Aichberger KJ, Mayerhofer M, et al. CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens. Am J Surg Pathol 2004;28:1319-25. 26. Schwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunol Allergy Clin North Am 2006;26:451-63.
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