Anaesthesia, 2004, 59, pages 695–703 .....................................................................................................................................................................................................................
REVIEW ARTICLE
Mast cell tryptase: a review of its physiology and clinical significance V. Payne1 and P. C. A. Kam2 1 Registrar, Department of Anaesthesia, 2 Professor of Anaesthesia, University of New South Wales, Department of Anaesthesia, St George Hospital, Kogarah, NSW 2217, Australia Summary
Mast cells, which are granulocytes found in peripheral tissue, play a central role in inflammatory and immediate allergic reactions. b-Tryptase is a neutral serine protease and is the most abundant mediator stored in mast cell granules. The release of b-tryptase from the secretory granules is a characteristic feature of mast cell degranulation. While its biological function has not been fully clarified, mast cell b-tryptase has an important role in inflammation and serves as a marker of mast cell activation. b-Tryptase activates the protease activated receptor type 2. It is involved in airway homeostasis, vascular relaxation and contraction, gastrointestinal smooth muscle activity and intestinal transport, and coagulation. Serum mast cell b-tryptase concentration is increased in anaphylaxis and in other allergic conditions. It is increased in systemic mastocytosis and other haematological conditions. Serum b-tryptase measurements can be used to distinguish mast cell-dependent reactions from other systemic disturbances such as cardiogenic shock, which can present with similar clinical manifestations. Increased b-tryptase levels are highly suggestive of an immunologically mediated reaction but may also occur following direct mast cell activation. Patients with increased mast cell b-tryptase levels must be investigated for an allergic cause. However, patients without increased mast cell tryptase levels should be investigated if the clinical picture suggests severe anaphylaxis. Keywords
Mast cell tryptase. Anaphylaxis. Mastocytosis. Immune response.
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Correspondence to: P. C. A. Kam E-mail:
[email protected] Accepted: 18 February 2004
Measurement of serum mast cell tryptase concentrations is used to distinguish mast cell-dependent reactions such as anaphylactic ⁄ anaphylactoid reactions during anaesthesia from other systemic disturbances which may present with similar clinical manifestations. However, serum mast cell concentrations can be increased in other conditions besides anaphylactic ⁄ anaphylactoid reactions to drugs. This review summarises the physiological and clinical significance of a patient with raised serum tryptase levels. Method
Published articles for this review were sourced by using a Medline search for the years 1980–2003. Key words used 2004 Blackwell Publishing Ltd
included tryptase, mast cell, adverse effects, anaphylaxis, mastocytosis. In addition, the Internet site for the National Library of Medicine PubMed (http://www. Asahq.org ⁄ PublicEeducation) was also searched using the above key words. Bibliographies of the included studies or articles were also searched for additional references (reference dredging). Physiology of mast cells
Mast cells are heavily granulated wandering cells found in connective tissues and are abundant beneath epithelial surfaces. Mast cells originate from CD34+ bone marrow precursor cells and circulate in the blood as precursors [1]. They are recruited into peripheral tissues such as the 695
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dermis of the skin, the lungs, and the mucosa and submucosa of the intestines, where they differentiate and mature. Mast cell growth factor is required for the development of mast cells. Mast cell granules contain heparin, histamine and many proteases such as tryptase. The extracellular release of mediators (histamine, heparin and many proteases), known as degranulation, may be induced by physical factors (mechanical trauma, high temperature), toxins, venoms, endogenous mediators (proteins, tissue proteases), and immune mechanisms (IgE dependent and IgE independent). IgE receptors are present on the mast cell membranes. When IgE-coated antigens bind to surface receptors, mast cell degranulation occurs. Increased mast cell tryptase has a central role in inflammatory and immediate allergic reactions initiated by immunoglobulins IgE. In addition, mast cells release tumour necrosis factor alpha (TNF-a) in response to bacterial products by an antibody-independent mechanism as part of innate immunity. IgE or IgG antibodies are generated by B-lymphocytes in response to the exposure to a specific antigen. IgE molecules bind to high affinity IgE receptors on the surface of mast cells. When these IgE molecules are bridged by re-introduced antigen, mast cell degranulation occurs, releasing both preformed and newly synthesised mediators. Under normal circumstances, these mediators help to orchestrate the development of a defensive acute inflammatory reaction. When there is massive release of these mediators, bronchoconstriction and vasodilation predominate. Complement activation can cause mast cell degranulation. Anaphylatoxins C5a, C3a and C4a are formed during complement activation. Activation of C5a receptors on the mast cell surface triggers degranulation. Inflammatory mediators in mast cells There are two main types of inflammatory mediators in mast cells. Preformed mediators such as histamine, proteoglycans (heparin, chondroitin sulphates) and neutral proteases (tryptase) stored in secretory granules are secreted upon mast cell activation. Newly generated mediators, including arachidonic acid metabolites such as leukotrienes and prostaglandins, cytokines, TNF and interleukins (IL)-4, IL-5 and IL-6 are absent in the resting mast cell, but are produced during IgE-mediated activation. There are two types of mast cells: • MCT mast cells contain only tryptase and are found predominantly in alveolar walls and the small intestinal mucosa; • MCCT mast cells containing both tryptase and chymase are present predominantly in the dermis of the skin, the intestinal submucosa and blood vessels. 696
Tryptase Mast cell tryptase is a tetrameric neutral serine protease with a molecular weight of 134 kDa. The genes encoding mast cell tryptase are located on the short arm of chromosome 16 [2]. The enzyme is made up of four non-covalently bound subunits, and each subunit has one active enzyme site. There are two main types of mast cell tryptase, a-tryptase and b-tryptase. There is approximately 90% sequence identity between the two types. b-Tryptases are classified into bI-, bII-, and bIII-tryptases, and the a-tryptases into aI- and aII-tryptases [2–4]. bII-tryptase is stored in the secretory granules of mast cells [5]. In contrast, a-protryptase is secreted constitutively from mast cells as an inactive proenzyme and is the major form of tryptase found in the blood of normal subjects. The activation of bII-protryptase involves two proteolytic steps [6, 7]. The first is an autocatalytic intermolecular cleavage, which occurs optimally at acidic pH and in the presence of heparin or dextran sulphate. The resulting product is a monomer, which is about 50 times less active than the final tetramer. The second step involves the removal of the remaining precursor dipeptide by dipeptidyl peptidase I, thus allowing the mature peptide spontaneously to form the active tetramer. This process also requires heparin or dextran sulphate [2]. The exact mechanism for the regulation of tryptase activity is unknown. The tetrameric structure of b-tryptase with the active site of each of the four monomers orientated towards the inner face of a central pore [8] makes it resistant to inactivation by biological inhibitors of serine proteases such as a-proteinase inhibitor, a2 macroglobulin and aprotinin [5]. Regulation is brought about by the slow dissociation of b-tryptase from heparin proteoglycan mediated by basic proteins such as antithrombin III [9]. The optimal pH for b-tryptase to process b-protryptase to b-pro’tryptase is 5.5–6.5 [6]. This is also the pH required to generate bradykinin from low molecular weight kininogen [10], and to degrade fibrinogen [11]. This pH range indicates that histidine residues play a critical role in this activation process [5]. b-tryptase is released at acidic tissues such as areas of poor vascularity or inflammation. Biological activities of mast cell tryptase Early investigations into the role of tryptase focussed on its ability to cleave certain extracellular substrates such as vasoactive intestinal peptide [12], calcitonin gene-related peptide [13], fibronectin [14] and kininogens [15]. Tryptase is a potent growth factor for epithelial cells, airway smooth muscle cells and fibroblasts [16–20]. During inflammation, tryptase can stimulate the release of granulocyte chemoattractant IL-8, and up-regulate expression of ICAM-1 on epithelial cells [16]. It induces 2004 Blackwell Publishing Ltd
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the expression of mRNA for IL-1b, which may be important for the recruitment of inflammatory cells to sites of mast cell activation [21]. Moreover, the release of tryptase from activated mast cells may stimulate secretion from neighbouring mast cells, thus providing an amplification signal [22]. He et al. found that total cellular histamine release by tryptase depended on the origin of the mast cells reflecting functional heterogeneity between mast cell populations [22]. The process is inactivated by heat, and is reduced by tryptase inhibitors such as AP366 and leupeptin. Thus, by acting as a stimulus for mast cell degranulation, b-tryptase plays a key role in allergic diseases by amplifying the responses of mast cells to allergens and other stimuli. Protease activated receptors Mast cell tryptase activates protease activated receptors (PAR) receptors. PARs are G-protein-coupled receptors, with seven transmembrane domain units [23]. PAR activation requires the proteolytic cleavage of the aminoterminus of the receptor. The newly formed N-terminal ‘tethered ligand’ interacts with the second extracellular loop of the receptor. This interaction triggers a sequence of events involving G-protein activation and intracellular signalling. Four PARs (PAR-1, PAR-2, PAR-3 and PAR-4) have been characterised. b-Tryptase activates the PAR-2 receptor [24, 25]. Berger et al. [26] discovered that PAR-2 activation mobilises intracellular calcium stores to increase intracellular Ca2+ via phosphoinositide phospholipase C activation and the inositol triphosphate pathway. PARs are expressed by airway epithelial and smooth muscle cells, endothelial and vascular smooth muscle cells, the terminal bronchial epithelium, type II pneumocytes, and mast cells within the respiratory tract [23]. Tryptase stimulates the release of bronchodilator and anti-inflammatory mediators. Although the large size of tryptase (130 kDa) may impair its diffusion or movement in extracellular fluid, it can be detected in broncho-alveolar lavage fluid. In the cardiovascular system, PAR-2 activation induces nitric oxide-mediated vascular relaxation [24]. PAR-2 agonists administered systemically in vivo cause transient hypotension. In endotoxaemic rats, PAR-2-mediated hypotension is enhanced and vascular PAR-2 mRNA levels are increased [27]. PAR-2 receptors are expressed by enterocytes and gastrointestinal smooth muscle cells in the small intestine, colon, liver and pancreas, and may have a role in regulating intestinal transport [28]. Mast cells are found within all layers of the walls of the gastrointestinal tract. Mast cell degranulation has been implicated in the pathogenesis of a number of diseases including inflammatory 2004 Blackwell Publishing Ltd
bowel disease, coeliac disease, food allergy and systemic mastocytosis [29]. Mast cell degranulation modulates intestinal chloride ion transport under normal conditions and in inflammatory bowel disease. It also causes motility disturbances [30]. Tryptase may have some role in the inflammation of pancreatitis when mast cells are present [31]. The role of tryptase and PAR-2 activation in mediating the release of neuropeptides from sensory neurones has been studied. It was found that 63% of sensory neurones express PAR-2 receptors, and up to 40% of them express substance P and CGRP [32, 33]. Tryptase causes excitation of sensory neurones, and this is indicated by a rise in intracellular calcium. Excitation of the sensory neurones stimulates the release of substance P and CGRP. These indicate that PAR-2 receptors on sensory neurones are critical to the inflammatory process, and that PAR-2 receptor antagonists may have a role as anti-inflammatory agents. There is evidence that mouse mast cell tryptase exhibits anticoagulant activity in vivo and in vitro due to its ability to degrade fibrinogen [34]. Fibrinogen is cleaved by tryptase in two sites, thus destroying the sequence motif that is recognised by cell surface integrins. Endothelial cell binding to tryptase-modified fibrinogen is significantly reduced [35]. Other experimental studies have found that genetically mast cell-deficient mice have a high susceptibility to ADP-induced thrombus formation and to cerebral thromboembolism [36, 37]. PAR receptors may act as links between blood coagulation and inflammation, including mast cell activation [38]. However, a recent study has demonstrated that the anticoagulant activity of the human tryptase ⁄ heparin complex is attributable exclusively to the heparin associated with the tryptase and not to intrinsic activity of the tryptase [39]. As such, mast cells probably do play a role in inhibiting thrombosis, but by mechanisms independent of the intrinsic activity of tryptase. Clinical utility of tryptase as an investigative tool
Tryptase levels in biological fluids have been used as indicators of mast cell number and activation [2]. The initial tryptase immunoassay used G5 monoclonal antibody (mAb) for capture (b-tryptase selective), and goat polyclonal antitryptase antibody preparation for detection, with a lower limit for detection of 2.5 ng.ml)1. This was used to detect tryptase released into the circulation of patients with anaphylaxis [40]. Following this, an immunoassay using the G5 mAb for capture and G4 mAb for detection was developed with a lower limit of detection of 1 ng.ml)1 [41]. Subsequently, new antitryptase mAb was produced and a new, more sensitive immunoassay 697
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was developed using the B12 mAb for capture and the same G4 mAb for detection [42]. This assay had a lower limit of detection of 0.5 ng.ml)1. With the development of recombinant forms of aIprotryptase and bII-tryptase the apparent discrepancy in baseline serum tryptase levels appeared to be resolved [2]. It became clear that G5 mAb recognised bIItryptase with greater sensitivity than aI-protryptase, whereas the B12 and G4 mAbs recognised the recombinant products of both tryptase genes equally [43]. Consequently, immunoassays using G5 mAbs detect bII-tryptase (possibly all b-tryptases), whereas those using the other mAbs detect total tryptase (a-pro and b-tryptases) [2]. An in vitro test system (UniCAP Tryptase, Pharmacia Diagnostics AB, Uppsala, Sweden) is commonly used to measure b-tryptase in human blood or plasma. It is a fluorescence immunoassay [44]. Antitryptase reacts with tryptase in the patient serum specimen. After washing, enzyme-labelled antibodies against b-tryptase are added to form a complex. After incubation, unbound enzymeantitryptase is washed away and the bound complex is incubated with a developing agent. At the end of the reaction the fluorescence is measured, and the degree of fluorescence correlates with the amount of tryptase present. The detection limit of this test is < 1.0 lg.l)1 (three standard deviations from zero concentration). Systemic anaphylaxis b-Tryptase levels in serum are elevated in most subjects with systemic anaphylaxis of sufficient severity to cause hypotension [40]. b-Tryptase is released from mast cells in parallel with histamine, but diffuses more slowly than histamine because it is associated with the protease– proteoglycan complex [2]. b-Tryptase levels peak at 15– 120 min and with a half-life of 1.5–2.5 h, whereas histamine levels peak at 5 min and decrease to baseline within 15–30 min. The practical significance of this is the window of opportunity for testing for systemic anaphylaxis. b-Tryptase testing can be performed on blood samples obtained 1–6 h after the onset of the reaction, compared with 15 min for histamine. High tryptase concentrations can be found in serum obtained from patients up to 3 days after death from suspected anaphylaxis [45]. b-Tryptase levels in serum were determined in possible cases of fatal systemic anaphylaxis within 24 h of death in 19 victims [46]. Levels > 10 ng.ml)1 were obtained in nine of nine victims after Hymenoptera (bee) stings, six of eight victims after food allergy and two of two victims after anaphylaxis to parenteral diagnostic ⁄ therapeutic agents. Levels were < 5 ng.ml)1 in 57 sequential sera collected postmortem from six control subjects. In general, b-tryptase levels 698
were much higher after parenteral compared with oral introduction of the allergen, in spite of the fatal outcome. In cases of clinical anaphylaxis with a normal level of b-tryptase, pathogenic mechanisms (basophil activation or complement-mediated anaphylactoid reactions) other than mast cell degranulation should be considered [2]. However, one study reported levels of b-tryptase >10 ng.ml)1 in five of 49 cases thought to be nonanaphylactic deaths [2]. One subject had coronary artery disease (b-tryptase 33 ng.ml)1). Three subjects who died of trauma had b-tryptase levels of 20, 24 and 106 ng.ml)1, respectively. Details regarding drugs received close to the time of death were not available. Careful consideration of the events near the time of death is needed to interpret postmortem levels of b-tryptase. Serum b-tryptase levels were measured in 30 consecutive patients presenting with a clinical allergic reaction of less than 6 h duration [47]. Anaphylaxis was diagnosed in 17 patients using clinical criteria and by immunological tests. b-Tryptase levels were significantly higher in this group than in the non-anaphylactic group (mostly patients with angioedema and urticaria). Serum b-tryptase levels ‡ 13.50 lg.l)1 are considered positive, giving a sensitivity of 35.29% (CI 15.73–59.51%) and specificity of 92.31% (CI 67.52–99.62%). Other allergic conditions Asthma is a complex inflammatory disorder involving a range of effector cells such as mast cells, macrophages, neutrophils, lymphocytes and eosinophils. Activated mast cells release mediators (TNF-a, IL-4, IL-5, IL-6 and IL-8), and this suggests that mast cells are involved in late asthmatic response and in the control of chronic inflammation. b-Tryptase is predominant enzyme in lung tissue [48]. In asthma, b-tryptase is usually overexpressed or released from mast cells prematurely. It causes a cascade of events such as airway inflammation and bronchoconstriction. A mutation of the b-tryptase gene causes the overexpression [48]. Sudden infant death syndrome Anaphylaxis has been suggested to be a cause of the sudden infant death syndrome (SIDS), although allergen sensitivity and mast cell activation have not been demonstrated [2]. Elevated postmortem levels of b-tryptase in victims of SIDS have been reported. Increased levels of a-tryptase have not been detected, suggesting that mast cell hyperplasia is not a feature of SIDS [49–51]. While no significant association has been found between antigenspecific IgE and b-tryptase levels, it is suggested that mast cell degranulation in SID occurred via IgE-independent mechanisms [2]. 2004 Blackwell Publishing Ltd
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Amniotic fluid embolism Amniotic fluid embolism is a rare clinical syndrome, with an estimated frequency of 1 : 8000–1 : 80 000 pregnancies [52]. The mortality (61–86%) is high for patients who are symptomatic [53, 54]. The definitive diagnosis of this syndrome should be made on the basis of clinical presentation and supportive laboratory studies. It has been suggested that amniotic fluid embolism may be the result of anaphylactic reactions to foetal antigens with mast cell degranulation and the release of chemical mediators. Increased pulmonary mast cells have been demonstrated in postmortem cases of amniotic fluid embolism [55]. A case study of an autopsy-proven fatal case of amniotic fluid embolism reported a significantly elevated serum b-tryptase level, suggesting possible mast cell activation [56]. However, there are other reported cases of amniotic fluid embolism diagnosed clinically whose tryptase levels were not elevated [57]. Other serological investigations include a significantly elevated level of sialyl Tn (a specific fetal antigen proposed as a diagnostic test for amniotic fluid embolism) and reduced levels of serum C3 and C4 [56, 57]. Systemic mastocytosis Systemic mastocytosis is characterised by mast cell hyperplasia in bone marrow, skin, liver, spleen and gastrointestinal mucosa. There are four recognised forms of systemic mastocytosis [58]. The indolent form (majority of cases) consists mainly of skin lesions such as urticaria pigmentosa, and does not alter life expectancy. The form associated with haematological disorders is more serious, with the prognosis determined by the nature of the accompanying disorder. In the aggressive form of the disease there is marked mast cell proliferation in the liver, spleen and lymph nodes, with eosinophilia in the affected organs and peripheral blood. This form has a poor prognosis due to widespread tissue infiltration. The last form, mast cell leukaemia, is rare and invariably fatal. It is characterised by circulating atypical mast cells. The clinical manifestations of the disease are caused by mast cell infiltration of tissues and the release of bioactive substances acting at both local and distant sites. Common signs and symptoms include pruritus, flushing, palpitations and urticaria pigmentosa. Multiple erythematous wheals due to focal accumulation of mast cells in the dermis may be present. Gastrointestinal manifestations include gastritis and peptic ulceration (caused by histamine-mediated hypersecretion of gastric acid), diarrhoea, abdominal pain and malabsorption (due to gut hypermotility). There may be mast cell-mediated fibrosis of the bone marrow, spleen and liver, the latter giving rise to portal hypertension and ascites. Neuropsychiatric manifestations include impairment of recent 2004 Blackwell Publishing Ltd
memory, reduced attention span and ‘migraine like’ headaches. The gold standard for diagnosis of mastocytosis is a tissue biopsy showing a pathological increase in the number of mast cells. However, the characteristic bone marrow lesions (paratrabecular collections of spindleshaped mast cells mixed with fibroblasts, mononuclear cells and eosinophils) are not always present. A study of tryptase levels in patients with biopsyproven mastocytosis reported concentrations of total tryptase > 20 ng.ml)1 and ratios of total tryptase to b-tryptase > 20, whereas normal patients had total tryptase levels < 14 ng.ml)1 [42]. The sensitivity of the total mast cell tryptase concentration as a diagnostic test is 83%, with a specificity of > 98%. Total serum tryptase concentrations may be useful in evaluating treatment aimed to reduce mast cell numbers in patients with systemic mastocytosis. Other haematological conditions Hypereosinophilic syndrome (HES) is a heterogeneous group of systemic diseases of unknown cause characterised by excessive eosinophils invading the heart, lungs, brain and nerves, causing organ damage. There are two major types of HES: a primary disorder of myelopoiesis, and a secondary eosinophilia caused by an overproduction of eosinophilopoietic cytokines by lymphocytes [59]. The clinical manifestations and responses to therapy in patients with HES are highly variable. Klion et al. examined the utility of serum tryptase levels in identifying a subset of patients with a primary myelopoietic disorder [59]. They found that patients with HES and elevated serum tryptase levels were more likely to develop fibroproliferative end organ damage and had a shorter life expectancy. However, they were also more likely to achieve clinical and haematological improvement when treated with imatinib, a tyrosine kinase inhibitor. Myelodysplastic syndrome (MDS) is a large group of acquired neoplastic disorders of the bone marrow most common in the elderly and is caused by an abnormal differentiation and maturation of haemopoietic cells. Serum tryptase levels can be used to differentiate the MDS variants. Elevated levels of total tryptase (a-tryptase and b-tryptase) are found in a group of patients with MDS [60]. Follow-up studies should clarify whether an elevated serum tryptase concentration in MDS is of prognostic significance. Role in anaesthesia
In the peri-operative period, multiple agents can cause anaphylaxis. These reactions are often dramatic and lifethreatening and it is crucial that the responsible agent is 699
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identified to avoid future anaphylaxis. Most anaesthetic drugs such as muscle relaxants are low molecular weight molecules and, as such, are considered haptens. Conjugation of the drug with a protein carrier and subsequent processing by antigen processing cells are the initial steps of sensitization, and can lead to formation of IgE antibodies to the hapten. With subsequent exposure to the drug, mast cells are activated, and anaphylaxis occurs. Anaphylactoid reactions also occur in anaesthesia due to release of mediators by other mechanisms. Anaphylactic reactions to anaesthetic and associated agents used during the peri-operative period have been reported with increasing frequency in most developed countries. Most reports on the incidence of anaphylaxis originate in Australia, France and New Zealand [61]. The estimated incidence of anaesthetic anaphylaxis was 1 : 10 000–20 000 in Australia in 1993 [62] and 1 : 13 000 in France in 1996 [61], with a mortality rate ranging from 3.5% to 4.7% [61, 63]. The prevalence of muscle relaxant sensitivity based on a positive skin test and ⁄ or detection of IgE antibodies to quaternary ammonium ions ranges from 1.6% to 16% [61, 64]. However the actual incidence of anaphylaxis to muscle relaxants has been estimated as 1 : 6500 for anaesthesia where a muscle relaxant is administered [61, 65]. Muscle relaxants are the most frequently involved anaesthetic-related drugs ⁄ agents that cause peri-operative anaphylaxis. In most series, succinylcholine is involved more frequently [61, 66–68] with rocuronium a common cause of anaphylactic reactions [69]. Other major causes of reaction are antibiotics, particularly penicillin and cephalosporins [66, 69], and colloids, particularly haemaccel [66] and latex [61]. An anaphylactic reaction must be suspected if unexplained hypotension, bronchospasm or angioedema occur during anaesthesia [45]. The likelihood of anaphylaxis is increased if more than one of these features is present, if they are associated with erythema, rash or urticaria, or the reaction is particularly severe. However, the classical symptoms of anaphylaxis are more commonly produced in anaesthesia by mechanisms other than true anaphylaxis. For example, the direct histamine releasing effects of anaesthetic drugs when injected rapidly may mimic anaphylaxis [66]. Fisher & Baldo investigated the value mast cell tryptase as a marker of anaphylaxis in anaesthesia using serum specimens from 350 patients after possible anaphylactic reactions during anaesthesia [66]. They showed that increased mast cell tryptase concentrations are a valuable indicator of an IgE-mediated anaphylactic reaction. IgE antibodies to drugs administered during anaesthesia were detected in 125 of 158 patients with increased mast cell tryptase concentrations but only seven of 143 patients who did not have an increase in mast cell tryptase had IgE 700
antibodies to these drugs. This may be caused by immunological release of anaphylactic mediators from basophils and not mast cells [70]. Although the data indicated that increased mast cell tryptase concentrations were associated with immunological reactions, increased mast cell tryptase levels can occur with direct histamine release [65]. The data from this study also indicated that the sampling time from the onset of the reaction should be 1–4 h rather than 1–6 h [65]. In a study investigating the prevalence of serum IgE antibodies against ammonium groups, choline, morphine, succinylcholine, thiopental and latex and increased mast cell tryptase concentrations in 18 patients who experienced an anaphylactic reaction during general anaesthesia, elevated tryptase concentrations were found in 12 of 18 patients [71]. Thirteen of 18 patients tested positive for IgE antibodies against ammonium ion and morphine. Ten of the 13 patients tested positive for IgE against succinylcholine, five tested positive for IgE against choline, and one against latex. Fifteen of the 18 patients tested positive for mast cell tryptase and ⁄ or specific IgE against neuromuscular blocking drugs (NMBD). Ten of the 18 patients experienced an IgE-mediated anaphylaxis to NMBD during anaesthesia, verified by detection of specific IgE and increased mast cell tryptase concentrations. There was a high incidence of cross-reactions between muscle relaxants and intradermal testing should be performed to determine the choice of muscle relaxants. However, the authors suggested that in all patients with a previous anaphylaxis during anaesthesia the anaesthetist should expect a new reaction to appear and undertake measures to handle the situation according to best practice. In conclusion, mast cell b-tryptase is a useful investigation after a possible anaphylactic reaction during anaesthesia. Blood samples for mast cell b-tryptase concentrations should be obtained between 1 and 4 h after the onset of the reaction, although increased mast cell concentrations may be detected up to 3 days postmortem [45]. Increased mast cell b-tryptase levels are highly suggestive of an immunologically mediated reaction but may reflect direct histamine release. Patients with increased mast cell b-tryptase levels must be investigated for an allergic cause, and patients without increased mast cell b-tryptase levels should be investigated if the clinical picture suggests severe anaphylaxis [66]. References 1 Krishnaswamy G, Kelley J, Johnson D, et al. The human mast cell: functions in physiology and disease. Frontiers in Bioscience 2001; 6: D1109–27.
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