Mastocytosis and Hymenoptera venom allergy Franziska Ruëff, Marianne Placzek and Bernhard Przybilla

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1 Mastocytosis and Hymenoptera venom allergy Franziska Ruëff, Marianne Placzek and Bernhard Przybilla Purpose of review Mastocytosis is a rare disease characterized by increased mast cells in skin and/or internal organs. We evaluate the impact of mastocytosis on diagnosis and treatment of Hymenoptera venom allergy. Recent findings Patients with Hymenoptera venom allergy who suffer from mastocytosis develop life-threatening sting reactions more often than those who do not. When patients with Hymenoptera venom allergy were systematically examined for mastocytosis, it was found to be represented to an abnormally high extent. Most patients with mastocytosis tolerate venom immunotherapy with no or only minor systemic symptoms. Venom immunotherapy was found to be marginally less effective in patients with mastocytosis than in those without evidence of mast cell disease (defined as absent cutaneous mastocytosis combined with a serum tryptase concentration of <11.4 mg/l). Several deaths from sting reactions were reported in patients with mastocytosis after venom immunotherapy was stopped. These patients should have venom immunotherapy for the rest of their lives. Summary Patients suffering from mastocytosis and Hymenoptera venom allergy are at risk from a particularly severe sting anaphylaxis. They need optimal diagnosis and treatment. In patients presenting with Hymenoptera venom allergy, screening tests by measurement of serum tryptase concentration, and a careful skin examination, are highly recommended. Keywords diagnosis, efficacy, Hymenoptera venom allergy, mastocytosis, sensitization, serum tryptase, side effects, venom immunotherapy Curr Opin Allergy Clin Immunol 6: ß 2006 Lippincott Williams & Wilkins. Department of Dermatology and Allergology, Ludwig-Maximilians University, Munich, Germany Correspondence to Professor Dr Franziska Ruëff, Department of Dermatology and Allergology, Ludwig-Maximilians University, Frauenlobstraße 9-11, München, Germany Tel: ; fax: ; Franziska.Rueff@med.uni-muenchen.de Current Opinion in Allergy and Clinical Immunology 2006, 6: Abbreviations HVA Hymenoptera venom allergy STC serum tryptase concentration VIT venom immunotherapy ß 2006 Lippincott Williams & Wilkins Introduction Two years ago this journal published a review by Dubois [1] addressing possible associations between mastocytosis and Hymenoptera venom allergy (HVA). Dubois and his group are known for their long-standing clinical experience with patients suffering from both mastocytosis and HVA. In his review [1] the author concluded that venom immunotherapy (VIT) in patients with mastocytosis is hampered by reduced safety and efficacy. According to personal observations and after reviewing the available literature, the author even questioned the benefit of VIT in these patients. In the current review, we will address the same issue, but from a very different perspective. It is our intention to provide evidence that patients with mastocytosis and HVA may not only benefit from VIT, but may even need it urgently as they are at risk from particularly severe anaphylaxis. It is well known that an elevated basal serum tryptase concentration (STC) is associated with very severe sting reactions [2 4]. An elevated STC is presumably a marker for mastocytosis. However, elevation of STC alone does not prove the diagnosis of mastocytosis, and must not, therefore, be equated with mastocytosis. In the following, we will focus on studies which assessed patients with proven mastocytosis. Classification and diagnosis of mastocytosis The term mastocytosis summarizes a group of diseases that are characterized by an increase of mast cells in the skin and/or internal organs (e.g. bone marrow, spleen, lever, lymph nodes, gut). Mast cells produce many mediators, which are released continuously (e.g. a-tryptase) or upon stimulation (e.g. histamine, b-tryptase, leukotrienes, cytokines). Mast cells have many important functions, especially for innate and adaptive immunity, inflammation and tissue remodelling [5,6]. Together with basophils they represent the most important effector cells of an acute, immediate reaction, such as acute sting anaphylaxis. Stem cell factor (KIT ligand) stimulates mast cells via a tyrosine kinase receptor (KIT) to grow and differentiate. In the pathogenesis of mastocytosis a mutation of the activating receptor KIT plays an eminent role. To date more than 10 different mutations have been found. In adults with systemic mastocytosis the predominant mutation is at codon 816, where asparagine is substituted by valine (D816V). This mutation causes the receptor to 284

2 Mastocytosis and Hymenoptera venom Ruëff et al. 285 be activated without the presence of a ligand. Receptor activation then leads to proliferation and enhanced survival of mast cells. Another abnormal feature in mastocytosis is the expression of certain adhesion molecules (CD2, CD25) on the cell surface. Expression of such molecules is absent in normal mast cells [7,8]. Some years ago a classification of mastocytosis was presented [9], which was later adopted by the World Health Organization. This classification differentiates between various types of cutaneous mastocytosis. Systemic mastocytosis may occur with or without cutaneous manifestation. The major criterion for the diagnosis of systemic mastocytosis is the finding of multifocal dense infiltrates of mast cells in bone marrow or in any other extracutaneous organ. Minor criteria are an abnormal morphology of extracutaneous mast cells, a mutation of the c-kit proto oncogene at codon 816 in an extracutaneous organ, expression of CD2 and/or CD25 on bone marrow mast cells and a STC of more than 20 mg/l. Elevated STC (>20 mg/l) is one of the four minor criteria for diagnosis of systemic mastocytosis. However, systemic mastocytosis may be present despite a STC level of <20 mg/l, or below the 95th percentile (11.4 mg/l). Consequently, cutaneous mastocytosis is not necessarily associated with elevated STC. On the other hand, an elevated STC may be found in other conditions, like chronic urticaria [10], chronic renal failure treated by haemodialysis [11] or haematologic diseases not associated with the mast cell lineage [12]. Despite these limitations, assessment of STC is a useful screening test for mastocytosis [13]. In addition, a careful skin examination should be performed to recognize cutaneous mastocytosis which may sometimes manifest with very inconspicuous lesions. If mastocytosis is suspected, further examinations will be necessary to confirm or exclude the diagnosis. Mastocytosis as a risk factor for Hymenoptera venom allergy Data on the frequency of HVA in patients with mastocytosis are scarce: in one study, one out of 21 patients with systemic mastocytosis (4.8%) had severe anaphylaxis after insect stings [14]. In another study, eight out of 40 patients with systemic mastocytosis (20%) presented with a history of a severe anaphylactic reaction, mostly occurring after Hymenoptera stings [15 ]. Similarly, there are also only a few data on the frequency of mastocytosis in patients with HVA. Among more than 2000 patients with HVA, systemic mastocytosis was diagnosed in approximately 1% [1]. From June 1998 to April 2004, 1102 patients were seen in our clinic with a history of an anaphylactic sting reaction. STC measurements and thorough skin assessments were performed on all patients. In case of an elevated basal STC (>11.4 mg/l; 95th percentile) and/or if cutaneous mastocytosis was suspected, we performed further examinations, primarily skin and bone marrow biopsies. We found an elevated STC in 106 patients (9.6%) and in 29 (2.6%) mastocytosis was diagnosed. Of these, 21 (72.4%) had cutaneous mastocytosis (in eight of them a bone marrow biopsy was not possible), and eight had systemic mastocytosis (27.6%). It is obvious that not all patients with mastocytosis present with visible skin lesions. Patient identification is also not facilitated by determining histamine metabolites in the urine, which has also been used as a screening test [1], or by an increased STC. Although some patients do show increased concentrations, the sensitivity and specificity of these tests remain imperfect. Thus mastocytosis might be missed by these screening examinations. So far, the true frequency of mastocytosis in patients with HVA is uncertain. The incidence of mastocytosis in the general population presumably amounts to seven new cases per persons each year [16]. Our results and those of Dubois [1] strongly suggest frequencies of mastocytosis to be significantly higher in patients with HVA than in the general population. Mastocytosis as a risk factor for severe sting reactions There are a number of case reports on very severe, partially fatal anaphylactic sting reactions in patients with cutaneous mastocytosis [13,17] or indolent systemic mastocytosis [1,15,17 21]. One study investigated the association between mastocytosis and the severity of previous sting reactions in 114 consecutive patients with HVA [3]. Thirty-eight patients had mild a systemic reaction limited to the skin, 39 patients had a moderate reaction with some internal organ involvement and 37 had developed a haemodynamic shock with consecutive loss of consciousness. An elevated basal STC (>13.5 mg/l; formerly given as the 95th percentile) was found in 2.5% of patients with mild, in 5.1% of those with moderate and in 21.6% of those with severe sting reactions. Cutaneous mastocytosis was diagnosed in 2.6% of patients with mild and moderate reaction (the same percentage for each group), but in 29.7% patients who had had a severe sting reaction [3]. We compared the severity of previous sting reactions in 55 patients with mastocytosis with that in 504 patients without evidence of mastocytosis (no cutaneous mastocytosis, STC <11.4 mg/l): 81.8% of the patients with mastocytosis had experienced anaphylactic shock or

3 286 Insect allergy near fatal reactions, whereas only 17.3% of the patients without evidence of mastocytosis had developed such severe reactions (P < 0.001) [22]. Therefore, it is beyond doubt that patients with mastocytosis and HVA are at a high risk from very severe or even fatal sting reactions. Pseudo-allergic sting reactions in patients with mastocytosis? There are several reports on patients with systemic mastocytosis with a history of severe sting reactions, but in whom venom-specific serum IgE was absent [17,19,23] or who additionally had also negative venom skin tests [1,15,24,25]. Also, in individual patients with cutaneous mastocytosis, venom sensitization could not be demonstrated by routine methods [24]. Such findings stimulated a hypothesis in which patients with mastocytosis and systemic sting reactions would actually not suffer from true HVA, but demonstrate a pseudo-allergy. The related mechanism, by which abundant mast cells release their mediators, was said to be toxic and would not involve IgE. If this hypothesis is true, virtually all patients with mastocytosis should uniformly experience systemic reactions after a sting from any member of the order Hymenoptera. This reaction should be most prominent in those patients presenting with a high mast cell burden in systemic mastocytosis. However, there are observations which militate against this hypothesis. First, not all patients with systemic mastocytosis develop anaphylactic sting reactions, and many of our patients with cutaneous mastocytosis or systemic mastocytosis and with simultaneous HVA react only to stings of one genus while tolerating stings of others. Second, the natural course of the disease is not in line with the pseudo-allergy hypothesis. Initially patients were found to tolerate stings despite the presence of systemic mastocytosis or cutaneous mastocytosis, whereas later on hypersensitivity reactions occurred [17,26,27]. Finally, we cannot confirm the finding that patients with mastocytosis and a history of a sting reaction are testnegative: in 52 out of 55 such patients (94.6%) venom sensitization could be identified by routine methods such as skin prick test, intradermal test or assessment of venom-specific serum IgE antibodies [22]. In the three remaining patients (one with cutaneous mastocytosis and two with systemic mastocytosis) venom sensitization was evident from results obtained by basophil histamine release tests or basophil activation tests [22]. It is possible that the purported absence of venom sensitization in patients with mastocytosis reflects a publication bias due to an underreporting of positive cases. The absence of sensitization according to results from routine tests does not exclude the possibility of its presence. Such a phenomenon is not limited to patients with mastocytosis. Absence of venom sensitization during routine testing is quite frequent in nonatopics [22] and is associated with longer time intervals since the last sting [22,28,29]. In addition, the absence of sensitization in a patient with HVA does not mean that the patient is cured [30]. In patients with mastocytosis who tested negative for venom in standard tests, it is essential to perform cellular tests. Two of our patients with mastocytosis only exhibited sensitization in cellular tests. Both underwent VIT and showed no anaphylactic reaction at a subsequent sting challenge. Patients with a definite history of systemic sting reactions would undergo VIT in our institution, even if venom sensitization could not be demonstrated by any method. Mastocytosis as a risk factor for side effects of venom immunotherapy There have been several case reports on patients with systemic mastocytosis who developed repeatedly severe anaphylactic reactions to VIT necessitating treatment stops [1,23,31]. Also, in small groups of patients with systemic mastocytosis, two out of four [23] or four out of seven patients [1] experienced such reactions during VIT, causing treatment to be stopped prematurely. In a small series of 10 patients with cutaneous mastocytosis or indolent systemic mastocytosis, VIT was tolerated well [24]. When patients with mastocytosis are treated in our institution, we routinely increase the dose according to a 4-day rush schedule and on an in-hospital basis. During dose increase we observed systemic reactions in 18.8% of 48 patients with mastocytosis, whereas only 9.3% of 494 patients without evidence of mastocytosis developed such adverse events (P < 0.05) [22]. However, the majority of these reactions were mild in patients with mastocytosis and did not require treatment other than antihistamines. Thus, side effects of VIT may be more frequent in patients with mastocytosis than in those without. However, this finding is of minor clinical relevance. The overall incidence of side effects in patients with mastocytosis is within a range which has been reported for a large cohort of unselected patients undergoing VIT [32]. However, if side effects occur, they may be very severe in individual patients. Thus, increasing the dose of VIT in patients with mastocytosis should be done on an inpatient basis for safety reasons. As these patients are endangered by life-threatening reactions, stopping treatment due to side effects should be considered only if all measures allowing a continuation of VIT have failed. Risk factors for side effects (e.g. type of mastocytosis, venom used for treatment, dose-increase schedule) need further evaluation.

4 Mastocytosis and Hymenoptera venom Ruëff et al. 287 Mastocytosis as a risk factor for treatment failure Mastocytosis has been also suspected of being associated with reduced efficacy of VIT. Six out of seven patients with indolent systemic mastocytosis developed an anaphylactic reaction to a field sting [1]. To monitor the efficacy of VIT we routinely perform a sting-challenge test with the culprit insect during the first year of VIT (about 6 12 months after reaching the maintenance dose). At this sting challenge 21.6% of 33 patients with mastocytosis developed a systemic reaction when on maintenance treatment with 100 mg of venom, whereas only 9.3% of 468 patients without evidence of mastocytosis turned out to be unprotected (P < 0.05) [33]. Importantly, the vast majority of subjects still reacting (including patients with mastocytosis) will be protected when the maintenance dose is increased (150 or 200 mg, or even higher if needed) [31]. Treatment with honeybee venom has been found to be less effective than VIT with vespid venom [34]. Therefore, the guidelines of the German Association of Allergy and Clinical Immunology (DGAKI) recommend extended therapy in patients with honeybee venom allergy and simultaneous mastocytosis. At the very least, these patients are to be treated with an elevated maintenance dose (usually 200 mg) from the start of VIT onwards [35]. An increased venom dose may also be considered in patients with vespid venom allergy who have additional risk factors (e.g. intense insect exposure). It is strongly recommended that the efficacy of VIT is assessed, particularly in patients with mastocytosis, by stingchallenge tests to identify those patients who are not protected by the preceding VIT [36]. Insect sting fatalities after discontinuation of venom immunotherapy Several groups have performed diagnostic sting-challenge tests in unselected patients with HVA 1 year or more after VIT has been stopped. Whereas some studies found that all patients were still protected [37,38], others reported systemic sting reactions in 5% [39], 10% [40,41] or 17.5% [42]. These studies did not address the question whether mastocytosis was a risk factor for a relapse of sting hypersensitivity. Oude Elberink and coworkers [18] reported two female patients with systemic mastocytosis and HVA who died from their allergy when stung again by a yellow jacket several years after discontinuation of VIT. One of them had received VIT for 5 years, and VIT had been stopped for the other after 2.5 years due to adverse effects. Reimers and Müller [21] reported on a male patient who had been successfully treated with honeybee VIT: honeybee stings which had occurred during and after VIT were well tolerated. Fifteen years after discontinuation of honeybee VIT the now 50-year-old patient died due to a reaction to a yellow jacket sting. Systemic mastocytosis was diagnosed at autopsy. The authors raised the question of whether VIT should be performed with honeybee as well as with vespid venom if patients with mastocytosis and HVA are to be treated. Such an approach might be more appropriate, even if sensitization to only one venom had been demonstrated before. It has been calculated that about 10% of patients treated with VIT for HVA will relapse 2 years after stopping VIT [43]. There is no guarantee of lifelong protection in all patients after discontinuation of VIT. It is unknown whether the risk of a relapse is higher in patients with mastocytosis than in those without. Since patients with mastocytosis are at a particularly high risk for severe sting reactions, it has been recommended to perform VIT in patients with mastocytosis and HVA for the rest of their lives [35]. Conclusion As mastocytosis is a rare disease, there were no systematic studies which examined a possible coincidence of mastocytosis and HVA in a large number of affected patients. Many aspects of diagnosis and treatment of HVA still need further evaluation in patients who suffer simultaneously from mastocytosis. Available information suggests that there are several ways by which mastocytosis could be a risk factor in the context of HVA: increased risk for developing HVA, severe or even lifethreatening sting reactions, and treatment failure. In the majority of patients with mastocytosis, VIT is tolerated without significant side effects. VIT is also effective. Even those patients who react to a re-sting test, despite preceding treatment, can be almost entirely protected by increasing the venom dose. We strongly recommend assessment of the therapeutic efficacy of VIT in mastocytosis by sting challenge. Only by doing so will it be possible to identify those patients who need a higher dose to reach treatment success. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp ). 1 Dubois AE. Mastocytosis and Hymenoptera allergy. Curr Opin Allergy Clin Immunol 2004; 4: Schwartz LB, Bradford TR, Rouse C, et al. Development of a new, more sensitive immunoassay for human tryptase: use in systemic anaphylaxis. J Clin Immunol 1994; 14: Ludolph-Hauser D, Ruëff F, Fries C, et al. Constitutionally raised serum concentrations of mast-cell tryptase and severe anaphylactic reactions to Hymenoptera stings. Lancet 2001; 357:

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