bs_bs_banner
Australasian Journal of Dermatology (2014) ••, ••–••
doi: 10.1111/ajd.12146
ORIGINAL RESEARCH
Disease spectrum in patients with elevated serum tryptase levels Elisabeth Aberer,1 Sandra Savic,1 Agnes Bretterklieber,1 Harald Reiter,1 Andrea Berghold2 and Werner Aberer1 1
Department of Dermatology and Venereology, Medical University of Graz, and 2Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
ABSTRACT Background: Elevated serum tryptase levels can be a sign of mastocytosis, which is a rare disease associated with systemic and/or skin manifestations. Objective: To investigate patients with elevated tryptase levels in regard to their underlying diseases, and to determine whether increased tryptase can be used as a diagnostic marker for underlying mastocytosis. Methods: In a retrospective study the data of 96 patients with serum tryptase levels higher than 15 μg/L were systematically analysed. In 48 patients control investigations for baseline tryptase were performed. Results: Fifty-three of the 96 patients had tryptase levels ≥20 μg/L. A mere 16% of the 96 patients suffered from mastocytosis and had the highest tryptase levels (P < 0.001). The remaining patients had anaphylaxis (36%), urticaria and angioedema (26%), local reactions to insect bites (4%), drug reactions (3%), or miscellaneous diagnoses (15%). Only 16 of these had acute symptoms at tryptase investigation. In all, 48 patients had a follow up; in 7/48 patients with acute symptoms normal tryptase levels were seen at control investigations, but 41/48 (85%) patients showed continuously elevated tryptase levels >15 μg/L and in 30 patients (62%) even values >20 μg/L; 11 of these patients had anaphylaxis, five urticaria, five other diagnoses and nine patients mastocytosis.
Correspondence: Dr Elisabeth Aberer, Department of Dermatology and Venerology, Medical University of Graz, Auenbruggerplatz 8, Graz A-8036, Austria. Email: elisabeth.aberer @medunigraz.at Elisabeth Aberer, MD, Sandra Savic, MD. Agnes Bretterklieber, MD. Harald Reiter, MD. Andrea Berghold, PhD. Werner Aberer, MD. Conflicts of interest: none. Submitted 23 September 2013; accepted 5 January 2014. © 2014 The Australasian College of Dermatologists
Conclusion: More than 50% of patients with nonmastocytosis such as urticaria and angioedema, drug or anaphylactic reactions repeatedly had tryptase levels higher than 20 μg/L. Since baseline tryptase >20 μg/L is a minor criterion for mastocytosis, these patients should be inspected for skin lesions of mastocytosis and receive a diagnostic body work-up for systemic mastocytosis including a bone marrow biopsy. Key words: anaphylaxis, mastocytosis, tryptase, urticaria.
INTRODUCTION Tryptase is a neutral protease, a mediator produced and secreted by mast cells (MC), and is released after the crosslinkage of immunoglobulin E-receptors with allergens or other degranulating agents. The degranulation of the mast cells can be mediated either immunologically or nonimmunologically.1–3 The appearance of tryptase in the blood most likely reflects mast cell activation.4 When serum tryptase levels increase significantly within 1 to 5 h after the initial signs of a suspected systemic hypersensitivity reaction, the condition is most likely allergic and of immunoglobulin E-mediated origin.2 After hymenoptera stings an increase in serum tryptase levels can be correlated with hypotension.4 Baseline serum tryptase levels in the absence of an allergic or anaphylactic reaction are interpreted as an indicator of the whole body mast cell load and, if elevated, may
Abbreviations: MC MCAS SM UP
mast cell mast cell activation syndrome systemic mastocytosis urticaria pigmentosa
2
E Aberer et al.
indicate the presence of systemic mastocytosis (SM).1 Tryptase levels may be increased in the presence of other diseases as well. Ferrer and colleagues reported that patients with chronic urticaria have significantly higher total serum tryptase levels than healthy people and atopic patients, and they found that tryptase levels were correlated with the severity of clinical symptoms.5 The median serum tryptase level in healthy adults is approximately 5 μg/L. Values >11.4 μg/L are regarded as potentially pathological. Severely impaired renal function may be associated with a moderate increase in tryptase.6 Nearly all patients with SM have persisting serum basal tryptase levels higher than 20 μg/L, which is a minor criterion of SM. The differential diagnosis of elevated tryptase levels includes myeloid non-MC-lineage neoplasms such as acute or chronic myeloid leukemia, myeloproliferative disorders, and myelodysplastic syndrome. In these patients, serum tryptase levels may be increased in the absence of a coexisting SM.6 On the other hand, normal tryptase levels do not rule out clonal mast cell disease. Mastocytosis is a skin or systemic disease with the potential involvement of several organs.7 The risk of anaphylactic reactions after an insect sting (or other causes of mast cell activation) is significantly higher in the presence of mastocytosis.8 Determining serum tryptase levels is basically a diagnostic and differential diagnostic parameter. It is also useful to monitor the course of disease. At the dermatological allergy outpatient clinic we frequently encounter patients with allergic reactions and elevated serum tryptase levels. However, at this time we do not know whether the patients have underlying mastocytosis. Clinically, they presently show or have a history of anaphylaxis, urticaria and angioedema and have different signs of mast cell activation such as pruritus, wheals, flushing, headache and gastrointestinal symptoms. It is unknown whether these patients have primary MC activation syndrome (MCAS) as seen in mastocytosis or a monoclonal MCAS, when monoclonal MC can be detected, secondary MCAS as seen in allergic, chronic inflammatory, or autoimmune diseases or idiopathic MCAS urticaria/ angioedema, idiopathic anaphylaxis or other diseases.8 The aim of this study was to characterise these patients’ underlying disease and determine how many of them had mastocytosis. Further, we wished to show that elevated tryptase levels can be used as a diagnostic marker for underlying mastocytosis, and to determine whether patients with a MCAS need to undergo a complete medical examination.
PATIENTS AND METHODS The present investigation was based on the retrospective data of patients who had attended the outpatient clinic for allergic diseases at the Department of Dermatology at the Medical University of Graz. Between July 2009 and May 2010, 3374 blood samples of patients with suspected MCAS were investigated for serum tryptase levels. Of the 3374 patients, 96 (3 %) had serum tryptase levels higher than 15 μg/L. (Fig. 1) Subsequently, 48 of the 96 patients were © 2014 The Australasian College of Dermatologists
3374 patients with signs of mast cell degranulation 96 patients with tryptase >15μg/L 16 patients with acute symptoms
80 patients without acute symptoms
48 patients reinvestigated 7 patients 15μg/L
30 patients with basal tryptase >20μg/L had anaphylaxis (11), urticaria (5), mastocytosis (9), other diagnoses (5) Figure 1
Flow chart of patients with tryptase >15 μg/L.
reinvestigated for their basal tryptase level from June 2010 to September 2012. Their clinical and laboratory data were analysed retrospectively. The patients’ clinical history was obtained from the medical document system. Data were entered in an Excel 2007 database and descriptive statistical analysis was performed. The project was approved by the local ethics committee.
RESULTS Serum tryptase levels Of 96 patients with elevated tryptase levels, seven had SM with skin involvement, five had SM without skin involvement, three had urticaria pigmentosa (UP), 35 anaphylaxis, 25 urticaria and angioedema, four had local reactions to insect stings, three had drug reactions and 14 had miscellaneous diagnoses (atopic dermatitis, psoriasis vulgaris, acne, acute and chronic pruritus, hereditary angioedema and swelling due to unknown causes) (Table 1). Of these patients 16 came with acute symptoms of urticaria (four), anaphylaxis after insect bite (eight), drug reaction (three) and exercise-induced urticaria/angioedema). Total serum tryptase levels in the 96 patients ranged between 15 and 195 μg/L; mean 27.7, median 21.0 (Fig. 2). In 43 patients the serum tryptase levels were between 15 and 20 μg/L, and in 53 patients they were more than 20 μg/L. Patients with mastocytosis had significantly higher tryptase levels than those with anaphylaxis, urticaria, angioedema or other diagnoses (P < 0.001) followed by patients with drug
Elevated tryptase in skin disease Table 1
3
Disease spectrum in patients with elevated tryptase Number of patients
Diagnosis Mastocytosis
Mastocytosis n = 15
Non-mastocytosis
Anaphylaxis Urticaria/angioedema Others (n = 21)
SM with skin involvement SM without skin involvement Urticaria pigmentosa
Increased local sting reactions Drug reactions Other diagnoses
Sex (M/F)
7 5
2/5 1/4
3 35 25 4
2/1 17/18 15/10 2/2
3 14
1/2 7/7
Age, years (mean, range)
Serum tryptase μg/L mean (range; median)
46 (30–73) 51 (42–70)
65.9 (19.0–195.0; 44.3) 53.5 (31.7–77.0; 48.6)
40 47 42 47
30.9 21.7 25.1 21.3
(24–51) (19–79) (18–98) (23–65)
76 (51–94) 48 (20–79)
(15.6–46.3; 30.9) (15.1–38.5; 19.2) (15.4–111.0; 20.0) (16.6–33.1; 17.8)
27.4 (17.9–44.1; 20.2) 19.9 (15.0–26.9; 19.2)
SM, systemic mastocytosis.
Serum tryptase levels (µg/L)
100
50
0 Anaphylaxis II-IV Figure 2 Table 2
Other
Comparison of serum tryptase levels in all 96 patients. Control tryptase investigations in 48 patients
Diagnosis
Number of patients
Acute event† History of anaphylaxis Urticaria Miscellaneous diagnoses Systemic mastocytosis Total
7 17 8 7 9 48
†
Urticaria / angioedema Systemic mastocytosis Diagnosis
Number of control samplings
Number of patients with tryptase 20 μg/L
Mean tryptase levels at control investigations (μg/L) min-max
1 2 2 1 3
7 0 0 0 0 7
0 11 5 5 9 30
4.3 (2.9–10.4) 22.2 (14.9–38.8) 20.4 (12.3–26.6) 19.6 (12.3–29.6) 58 (23.3–163)
to to to to to
3 8 14 6 6
anaphylaxis, acute urticaria, acute insect bite reaction, exercise induced urticaria, systemic mastocytosis.
reactions, urticaria or angioedema, anaphylaxis, increased local reactions to a sting and others (Fig. 2) (Table 1). Basal tryptase, reinvestigated in 48/96 patients, showed a decrease of tryptase 15 μg/L (85%) and 30/48 patients had even higher values >20 μg/L (62%). Of the 30 patients with higher values, 11 had a history of anaphylaxis, five had urticaria, five had miscellaneous diagnoses and nine had mastocytosis. © 2014 The Australasian College of Dermatologists
4
E Aberer et al.
Table 3
Results of body work-up in patients with elevated tryptase
Diagnosis
Mastocytosis
Investigations (pathological/performed)
SM with skin involvement n=7
Osteodensitometry (8/13)
Bone scintigraphy (2/24)
Bone marrow biopsy (12/22)
Kit gene mutation (3/10)
Abdominal sonography (3/44)
2 osteoporosis
1 BM involvement
7 positive
3 positive
1 splenomegaly
2 osteopenia
1 central bone marrow activation 4 normal 1 n.d. 1BM involvement
1 n.c.
6 normal
2 negative
3 normal
3 n.d. SM without skin involvement n=5
Nonmastocytosis
1 normal 4 n.d.
2 2 1 2 1
normal n.d. normal n.d. n.c.
Urticaria pigmentosa n=3 Anaphylaxis
3 n.d.
n = 35
1 osteopenia 4 normal 29 n.d.
7 normal 27 n.d.
Urticaria/ angioedema n = 25
1 osteoporosis
3 normal
24 n.d.
22 n.d.
Increased local sting reactions n=4 Other diagnoses n = 14 Drug reactions n=3
4 n.d.
1 n.c.
1 osteopenia 13 n.d. 3 n.d.
3 n.d. 2 normal 12 n.d. 3 n.d.
1 osteoporosis
5 positive
2 n.d. 1 negative 2 n.d. 3 negative
1 negative 2 n.d. 2 negative
1 not usable 1 20 μg/L. Bone marrow involvement of SM could be proven in 12 patients. (Table 3) In the non-mastocytosis group, the bone marrow biopsies were negative or unspecific for mastocytosis in eight patients (including one patient who had a small diffuse mast cell infiltration, one with a non-specific reactive change and one with 15 μg/L, only 16% had different forms of SM. The tryptase levels were significantly higher than in patients with anaphylaxis, urticaria or other diagnoses (P < 0.001); and only 16 of the latter patients came with an acute episode. It is remarkable that more than 50% of patients with non-mastocytosis had tryptase levels higher than 20 μg/L; these were patients with drug reactions, followed by those with urticaria and angioedema. The next in line were those with a history of anaphylaxis and increased local reactions after insect stings and finally, patients with various other diagnoses. Tryptase was continuously elevated in 85% of the reinvestigated patients. Although this was a retrospective study, we assume that these patient’s values were the basal tryptase. In Brockow and colleagues’ study, serum tryptase levels were higher in mastocytosis patients with anaphylaxis, indicating an association with the severity of systemic involvement. Higher serum tryptase values reflect a higher total systemic mast cell count and pool of effector cells, possibly leading to a higher risk of spontaneous mast cell degranulation.9,10 Altogether, 46% of our patients with elevated tryptase levels had anaphylaxis or a history of anaphylactic reactions, including 33% of patients with UP, 42% of those with SM with skin involvement, and as many as 100% (all five) of those with SM without skin involvement. Two patients with SM without skin involvement had type IV anaphylaxis. These data concur with those reported by Brockow and colleagues, who found that the risk of anaphylaxis was higher in patients with no cutaneous lesions than in those with cutaneous lesions of UP. On the other hand, patients
5
with severe grade IV anaphylaxis and increased tryptase levels are likely to suffer from underlying mastocytosis. The causes of anaphylaxis in mastocytosis do not differ from triggers of anaphylaxis in patients without mastocytosis. These are hymenoptera stings, food and medications.9 Our anaphylaxis and mastocytosis patients had similar causes of anaphylaxis, namely bee and wasp venom, food and nonsteroid anti-rheumatic drugs. Ruëff and colleagues reported that, in patients with hymenoptera venom allergy, baseline serum tryptase is associated with the risk of severe anaphylactic reactions. After a field sting 21% of their patients had severe anaphylactic reactions and the frequency of this event increased significantly in direct proportion to rising tryptase concentrations.11 These observations agree with our data: 23% of our patients with increased tryptase levels had a history of severe allergic reactions defined as grade III and IV reactions. The most important problem for patients with elevated tryptase is the rather high risk (24%) of systemic side effects during venom immunotherapy.12 Even minor increases in baseline serum tryptase levels are associated with more frequent severe systemic reactions during the build-up phase, especially in patients allergic to wasp venom. Screening serum baseline tryptase levels is routine in our clinical practice for patients with systemic reactions caused by hymenoptera stings and before the administration of venom immunotherapy. However, the entire diagnostic work-up for SM is usually performed only in patients with the typical skin lesions of cutaneous mastocytosis. De Olano and colleagues found that 76% of patients with a hymenoptera venom allergy and SM do not have skin involvement.13 Hence, it is suggested that patients with elevated baseline tryptase and systemic reactions to hymenoptera stings should be investigated for SM as well. An entire work-up for mastocytosis was performed in some of our anaphylaxis and urticaria/angioedema patients. A bone marrow biopsy was performed in nine of these, showing pathological although not specific changes in four patients, such as elevated mast cell count, reactive changes and myelodysplasia. In all, 70% of our patients with UP skin lesions had a positive bone marrow biopsy. This correlates with data reported by Topar and colleagues, who found that 60% of patients with UP had mast cell infiltrates in their bone marrow.14 However, the authors report that bone marrow involvement in UP patients does not appear to correlate with the clinical symptoms of mast cell activation and therefore they express doubts as to whether bone marrow biopsies are useful to decide on further medical treatment. We believe that knowledge of bone marrow involvement is important for two reasons. The first is that one may anticipate very severe anaphylactic reactions in these patients. This fact is relevant for immunotherapy as well as in respect of situations involving a risk for mast cell degranulation, such as after the administration of certain drugs.15 Secondly, patients with a c-KIT mutation are subject to the risk of disease progression and are likely to develop more aggressive forms of disease that need periodic follow-up investigations.15,16 Three of our patients with skin involvement had © 2014 The Australasian College of Dermatologists
6
E Aberer et al.
a c-KIT gene mutation and were candidates for regular monitoring. On the other hand, Escribano and colleagues reported that indolent SM in adults is associated with a low rate of disease progression rate, and the large majority of these patients have a normal life expectancy.16 In three patients hepatomegaly or splenomegaly was noted, one in SM and two in non-mastocytosis patients; one of whom had anaphylaxis the other urticaria and angioedema. In Barete and colleagues’ large group of SM patients, half of the patients had bone involvement and osteoporosis was the most common bone manifestation (31%).17 In our 12 SM patients, one-third of the patients had bone involvement. Also in our non-mastocytosis patients osteoporosis was found in two and osteopenia in two patients (4/8 patients, 50%), which is a high number since the mean age of the patients was 20 μg/L is a minor criterion of mastocytosis, a bone marrow biopsy should also be per© 2014 The Australasian College of Dermatologists
formed. Further, these patients should be advised about their increased risk of severe anaphylactic reactions after hymenoptera bites and certain drugs.
ACKNOWLEDGEMENTS This project was sponsored by the Austrian Society of Dermatology and Venereology. We thank Marion Herzl for supplying the tryptase data.
REFERENCES 1.
2. 3.
4. 5.
6.
7. 8.
9.
10.
11.
12.
13.
14.
15.
16.
Tharp MD. Mastocytosis. In: Bolognia JL, Jorizzo JL, Rapini RP (eds). Dermatology, 2nd edn. St Louis, MO: Mosby Elsevier, 2008; 1845–53. Müller UR. Elevated baseline serum tryptase, mastocytosis and anaphylaxis. Clin. Exp. Allergy 2009; 39: 620–2. Komericki P, Arbab E, Grims R et al. Tryptase as severity marker in drug provocation tests. Int. Arch. Allergy Immunol. 2006; 140: 164–9. Caughey GH. Tryptase genetics and anaphylaxis. J. Allergy Clin. Immunol. 2006; 117: 1411–4. Ferrer M, Núñez- Cordoba JM, Luquin E et al. Serum total tryptase levels are increased in patients with active chronic urticaria. Clin. Exp. Allergy 2010; 40: 1760–6. Valent P, Akin C, Escribano L et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur. J. Clin. Invest. 2007; 37: 435–53. Amon U, Hartmann K, Horny HP et al. Mastocytosis – an update. J. Dtsch. Dermatol. Ges. 2010; 8: 695–711. Akin C, Valent P, Metcalfe D. Mast cell activation syndrome: proposed diagnostic criteria. J. Allergy Clin. Immunol. 2010; 126: 1099–104. Brockow K, Jofer C, Behrendt H et al. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy 2008; 63: 226–32. Schwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunol. Allergy Clin. North Am. 2006; 26: 451– 63. Ruëff F, Przybilla B, Bilo MB et al. Predictors of severe systematic 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. Ruëff F, Przybilla B, Biló MB 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: 105–11. de Olano DG, Caballer B, Núñez-Lopez R 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. Topar G, Staudacher C, Geisen F et al. Urticaria pigmentosa: a clinical, hematopathologic, and serologic study of 30 adults. Am. J. Clin. Pathol. 1998; 109: 279–85. Bonadonna P, Perbellini O, Passalacqua G 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. Escribano L, Alvarez-Twose I, Sánchez-Muñoz L 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.
Elevated tryptase in skin disease 17.
18. 19.
20.
Barete S, Assous N, de Gennes C et al. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann. Rheum. Dis. 2010; 69: 1838–41. Nguyen BD. CT and scintigraphy of aggressive lymphadenopathic mastocytosis. Am. J. Roentgenol. 2002; 178: 769–70. Chen CC, Andrich MP, Mican JM et al. A retrospective analysis of bone scan abnormalities in mastocytosis: correlation with disease category and prognosis. J. Nucl. Med. 1994; 35: 1471–5. Valent P, Horny HP, Triggiani M et al. Clinical and laboratory parameters of mast cell activation as basis for the formulation of diagnostic criteria. Int. Arch. Allergy Immunol. 2011; 156: 119–27. Review.
21.
22.
23.
7
Metcalfe DD. Differential diagnosis of the patient with unexplained flushing/anaphylaxis. Allergy Asthma Proc. 2000; 21: 21–4. Review. Schwartz LB, Sakai K, Bradford TR 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. Valent P, Aberer E, Beham-Schmid C 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.
© 2014 The Australasian College of Dermatologists
Australasian Journal of Dermatology (2014) ••, ••–••
doi: 10.1111/ajd.12146
ORIGINAL RESEARCH
Disease spectrum in patients with elevated serum tryptase levels Elisabeth Aberer,1 Sandra Savic,1 Agnes Bretterklieber,1 Harald Reiter,1 Andrea Berghold2 and Werner Aberer1 1
Department of Dermatology and Venereology, Medical University of Graz, and 2Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
ABSTRACT Background: Elevated serum tryptase levels can be a sign of mastocytosis, which is a rare disease associated with systemic and/or skin manifestations. Objective: To investigate patients with elevated tryptase levels in regard to their underlying diseases, and to determine whether increased tryptase can be used as a diagnostic marker for underlying mastocytosis. Methods: In a retrospective study the data of 96 patients with serum tryptase levels higher than 15 μg/L were systematically analysed. In 48 patients control investigations for baseline tryptase were performed. Results: Fifty-three of the 96 patients had tryptase levels ≥20 μg/L. A mere 16% of the 96 patients suffered from mastocytosis and had the highest tryptase levels (P < 0.001). The remaining patients had anaphylaxis (36%), urticaria and angioedema (26%), local reactions to insect bites (4%), drug reactions (3%), or miscellaneous diagnoses (15%). Only 16 of these had acute symptoms at tryptase investigation. In all, 48 patients had a follow up; in 7/48 patients with acute symptoms normal tryptase levels were seen at control investigations, but 41/48 (85%) patients showed continuously elevated tryptase levels >15 μg/L and in 30 patients (62%) even values >20 μg/L; 11 of these patients had anaphylaxis, five urticaria, five other diagnoses and nine patients mastocytosis.
Correspondence: Dr Elisabeth Aberer, Department of Dermatology and Venerology, Medical University of Graz, Auenbruggerplatz 8, Graz A-8036, Austria. Email: elisabeth.aberer @medunigraz.at Elisabeth Aberer, MD, Sandra Savic, MD. Agnes Bretterklieber, MD. Harald Reiter, MD. Andrea Berghold, PhD. Werner Aberer, MD. Conflicts of interest: none. Submitted 23 September 2013; accepted 5 January 2014. © 2014 The Australasian College of Dermatologists
Conclusion: More than 50% of patients with nonmastocytosis such as urticaria and angioedema, drug or anaphylactic reactions repeatedly had tryptase levels higher than 20 μg/L. Since baseline tryptase >20 μg/L is a minor criterion for mastocytosis, these patients should be inspected for skin lesions of mastocytosis and receive a diagnostic body work-up for systemic mastocytosis including a bone marrow biopsy. Key words: anaphylaxis, mastocytosis, tryptase, urticaria.
INTRODUCTION Tryptase is a neutral protease, a mediator produced and secreted by mast cells (MC), and is released after the crosslinkage of immunoglobulin E-receptors with allergens or other degranulating agents. The degranulation of the mast cells can be mediated either immunologically or nonimmunologically.1–3 The appearance of tryptase in the blood most likely reflects mast cell activation.4 When serum tryptase levels increase significantly within 1 to 5 h after the initial signs of a suspected systemic hypersensitivity reaction, the condition is most likely allergic and of immunoglobulin E-mediated origin.2 After hymenoptera stings an increase in serum tryptase levels can be correlated with hypotension.4 Baseline serum tryptase levels in the absence of an allergic or anaphylactic reaction are interpreted as an indicator of the whole body mast cell load and, if elevated, may
Abbreviations: MC MCAS SM UP
mast cell mast cell activation syndrome systemic mastocytosis urticaria pigmentosa
2
E Aberer et al.
indicate the presence of systemic mastocytosis (SM).1 Tryptase levels may be increased in the presence of other diseases as well. Ferrer and colleagues reported that patients with chronic urticaria have significantly higher total serum tryptase levels than healthy people and atopic patients, and they found that tryptase levels were correlated with the severity of clinical symptoms.5 The median serum tryptase level in healthy adults is approximately 5 μg/L. Values >11.4 μg/L are regarded as potentially pathological. Severely impaired renal function may be associated with a moderate increase in tryptase.6 Nearly all patients with SM have persisting serum basal tryptase levels higher than 20 μg/L, which is a minor criterion of SM. The differential diagnosis of elevated tryptase levels includes myeloid non-MC-lineage neoplasms such as acute or chronic myeloid leukemia, myeloproliferative disorders, and myelodysplastic syndrome. In these patients, serum tryptase levels may be increased in the absence of a coexisting SM.6 On the other hand, normal tryptase levels do not rule out clonal mast cell disease. Mastocytosis is a skin or systemic disease with the potential involvement of several organs.7 The risk of anaphylactic reactions after an insect sting (or other causes of mast cell activation) is significantly higher in the presence of mastocytosis.8 Determining serum tryptase levels is basically a diagnostic and differential diagnostic parameter. It is also useful to monitor the course of disease. At the dermatological allergy outpatient clinic we frequently encounter patients with allergic reactions and elevated serum tryptase levels. However, at this time we do not know whether the patients have underlying mastocytosis. Clinically, they presently show or have a history of anaphylaxis, urticaria and angioedema and have different signs of mast cell activation such as pruritus, wheals, flushing, headache and gastrointestinal symptoms. It is unknown whether these patients have primary MC activation syndrome (MCAS) as seen in mastocytosis or a monoclonal MCAS, when monoclonal MC can be detected, secondary MCAS as seen in allergic, chronic inflammatory, or autoimmune diseases or idiopathic MCAS urticaria/ angioedema, idiopathic anaphylaxis or other diseases.8 The aim of this study was to characterise these patients’ underlying disease and determine how many of them had mastocytosis. Further, we wished to show that elevated tryptase levels can be used as a diagnostic marker for underlying mastocytosis, and to determine whether patients with a MCAS need to undergo a complete medical examination.
PATIENTS AND METHODS The present investigation was based on the retrospective data of patients who had attended the outpatient clinic for allergic diseases at the Department of Dermatology at the Medical University of Graz. Between July 2009 and May 2010, 3374 blood samples of patients with suspected MCAS were investigated for serum tryptase levels. Of the 3374 patients, 96 (3 %) had serum tryptase levels higher than 15 μg/L. (Fig. 1) Subsequently, 48 of the 96 patients were © 2014 The Australasian College of Dermatologists
3374 patients with signs of mast cell degranulation 96 patients with tryptase >15μg/L 16 patients with acute symptoms
80 patients without acute symptoms
48 patients reinvestigated 7 patients 15μg/L
30 patients with basal tryptase >20μg/L had anaphylaxis (11), urticaria (5), mastocytosis (9), other diagnoses (5) Figure 1
Flow chart of patients with tryptase >15 μg/L.
reinvestigated for their basal tryptase level from June 2010 to September 2012. Their clinical and laboratory data were analysed retrospectively. The patients’ clinical history was obtained from the medical document system. Data were entered in an Excel 2007 database and descriptive statistical analysis was performed. The project was approved by the local ethics committee.
RESULTS Serum tryptase levels Of 96 patients with elevated tryptase levels, seven had SM with skin involvement, five had SM without skin involvement, three had urticaria pigmentosa (UP), 35 anaphylaxis, 25 urticaria and angioedema, four had local reactions to insect stings, three had drug reactions and 14 had miscellaneous diagnoses (atopic dermatitis, psoriasis vulgaris, acne, acute and chronic pruritus, hereditary angioedema and swelling due to unknown causes) (Table 1). Of these patients 16 came with acute symptoms of urticaria (four), anaphylaxis after insect bite (eight), drug reaction (three) and exercise-induced urticaria/angioedema). Total serum tryptase levels in the 96 patients ranged between 15 and 195 μg/L; mean 27.7, median 21.0 (Fig. 2). In 43 patients the serum tryptase levels were between 15 and 20 μg/L, and in 53 patients they were more than 20 μg/L. Patients with mastocytosis had significantly higher tryptase levels than those with anaphylaxis, urticaria, angioedema or other diagnoses (P < 0.001) followed by patients with drug
Elevated tryptase in skin disease Table 1
3
Disease spectrum in patients with elevated tryptase Number of patients
Diagnosis Mastocytosis
Mastocytosis n = 15
Non-mastocytosis
Anaphylaxis Urticaria/angioedema Others (n = 21)
SM with skin involvement SM without skin involvement Urticaria pigmentosa
Increased local sting reactions Drug reactions Other diagnoses
Sex (M/F)
7 5
2/5 1/4
3 35 25 4
2/1 17/18 15/10 2/2
3 14
1/2 7/7
Age, years (mean, range)
Serum tryptase μg/L mean (range; median)
46 (30–73) 51 (42–70)
65.9 (19.0–195.0; 44.3) 53.5 (31.7–77.0; 48.6)
40 47 42 47
30.9 21.7 25.1 21.3
(24–51) (19–79) (18–98) (23–65)
76 (51–94) 48 (20–79)
(15.6–46.3; 30.9) (15.1–38.5; 19.2) (15.4–111.0; 20.0) (16.6–33.1; 17.8)
27.4 (17.9–44.1; 20.2) 19.9 (15.0–26.9; 19.2)
SM, systemic mastocytosis.
Serum tryptase levels (µg/L)
100
50
0 Anaphylaxis II-IV Figure 2 Table 2
Other
Comparison of serum tryptase levels in all 96 patients. Control tryptase investigations in 48 patients
Diagnosis
Number of patients
Acute event† History of anaphylaxis Urticaria Miscellaneous diagnoses Systemic mastocytosis Total
7 17 8 7 9 48
†
Urticaria / angioedema Systemic mastocytosis Diagnosis
Number of control samplings
Number of patients with tryptase 20 μg/L
Mean tryptase levels at control investigations (μg/L) min-max
1 2 2 1 3
7 0 0 0 0 7
0 11 5 5 9 30
4.3 (2.9–10.4) 22.2 (14.9–38.8) 20.4 (12.3–26.6) 19.6 (12.3–29.6) 58 (23.3–163)
to to to to to
3 8 14 6 6
anaphylaxis, acute urticaria, acute insect bite reaction, exercise induced urticaria, systemic mastocytosis.
reactions, urticaria or angioedema, anaphylaxis, increased local reactions to a sting and others (Fig. 2) (Table 1). Basal tryptase, reinvestigated in 48/96 patients, showed a decrease of tryptase 15 μg/L (85%) and 30/48 patients had even higher values >20 μg/L (62%). Of the 30 patients with higher values, 11 had a history of anaphylaxis, five had urticaria, five had miscellaneous diagnoses and nine had mastocytosis. © 2014 The Australasian College of Dermatologists
4
E Aberer et al.
Table 3
Results of body work-up in patients with elevated tryptase
Diagnosis
Mastocytosis
Investigations (pathological/performed)
SM with skin involvement n=7
Osteodensitometry (8/13)
Bone scintigraphy (2/24)
Bone marrow biopsy (12/22)
Kit gene mutation (3/10)
Abdominal sonography (3/44)
2 osteoporosis
1 BM involvement
7 positive
3 positive
1 splenomegaly
2 osteopenia
1 central bone marrow activation 4 normal 1 n.d. 1BM involvement
1 n.c.
6 normal
2 negative
3 normal
3 n.d. SM without skin involvement n=5
Nonmastocytosis
1 normal 4 n.d.
2 2 1 2 1
normal n.d. normal n.d. n.c.
Urticaria pigmentosa n=3 Anaphylaxis
3 n.d.
n = 35
1 osteopenia 4 normal 29 n.d.
7 normal 27 n.d.
Urticaria/ angioedema n = 25
1 osteoporosis
3 normal
24 n.d.
22 n.d.
Increased local sting reactions n=4 Other diagnoses n = 14 Drug reactions n=3
4 n.d.
1 n.c.
1 osteopenia 13 n.d. 3 n.d.
3 n.d. 2 normal 12 n.d. 3 n.d.
1 osteoporosis
5 positive
2 n.d. 1 negative 2 n.d. 3 negative
1 negative 2 n.d. 2 negative
1 not usable 1 20 μg/L. Bone marrow involvement of SM could be proven in 12 patients. (Table 3) In the non-mastocytosis group, the bone marrow biopsies were negative or unspecific for mastocytosis in eight patients (including one patient who had a small diffuse mast cell infiltration, one with a non-specific reactive change and one with 15 μg/L, only 16% had different forms of SM. The tryptase levels were significantly higher than in patients with anaphylaxis, urticaria or other diagnoses (P < 0.001); and only 16 of the latter patients came with an acute episode. It is remarkable that more than 50% of patients with non-mastocytosis had tryptase levels higher than 20 μg/L; these were patients with drug reactions, followed by those with urticaria and angioedema. The next in line were those with a history of anaphylaxis and increased local reactions after insect stings and finally, patients with various other diagnoses. Tryptase was continuously elevated in 85% of the reinvestigated patients. Although this was a retrospective study, we assume that these patient’s values were the basal tryptase. In Brockow and colleagues’ study, serum tryptase levels were higher in mastocytosis patients with anaphylaxis, indicating an association with the severity of systemic involvement. Higher serum tryptase values reflect a higher total systemic mast cell count and pool of effector cells, possibly leading to a higher risk of spontaneous mast cell degranulation.9,10 Altogether, 46% of our patients with elevated tryptase levels had anaphylaxis or a history of anaphylactic reactions, including 33% of patients with UP, 42% of those with SM with skin involvement, and as many as 100% (all five) of those with SM without skin involvement. Two patients with SM without skin involvement had type IV anaphylaxis. These data concur with those reported by Brockow and colleagues, who found that the risk of anaphylaxis was higher in patients with no cutaneous lesions than in those with cutaneous lesions of UP. On the other hand, patients
5
with severe grade IV anaphylaxis and increased tryptase levels are likely to suffer from underlying mastocytosis. The causes of anaphylaxis in mastocytosis do not differ from triggers of anaphylaxis in patients without mastocytosis. These are hymenoptera stings, food and medications.9 Our anaphylaxis and mastocytosis patients had similar causes of anaphylaxis, namely bee and wasp venom, food and nonsteroid anti-rheumatic drugs. Ruëff and colleagues reported that, in patients with hymenoptera venom allergy, baseline serum tryptase is associated with the risk of severe anaphylactic reactions. After a field sting 21% of their patients had severe anaphylactic reactions and the frequency of this event increased significantly in direct proportion to rising tryptase concentrations.11 These observations agree with our data: 23% of our patients with increased tryptase levels had a history of severe allergic reactions defined as grade III and IV reactions. The most important problem for patients with elevated tryptase is the rather high risk (24%) of systemic side effects during venom immunotherapy.12 Even minor increases in baseline serum tryptase levels are associated with more frequent severe systemic reactions during the build-up phase, especially in patients allergic to wasp venom. Screening serum baseline tryptase levels is routine in our clinical practice for patients with systemic reactions caused by hymenoptera stings and before the administration of venom immunotherapy. However, the entire diagnostic work-up for SM is usually performed only in patients with the typical skin lesions of cutaneous mastocytosis. De Olano and colleagues found that 76% of patients with a hymenoptera venom allergy and SM do not have skin involvement.13 Hence, it is suggested that patients with elevated baseline tryptase and systemic reactions to hymenoptera stings should be investigated for SM as well. An entire work-up for mastocytosis was performed in some of our anaphylaxis and urticaria/angioedema patients. A bone marrow biopsy was performed in nine of these, showing pathological although not specific changes in four patients, such as elevated mast cell count, reactive changes and myelodysplasia. In all, 70% of our patients with UP skin lesions had a positive bone marrow biopsy. This correlates with data reported by Topar and colleagues, who found that 60% of patients with UP had mast cell infiltrates in their bone marrow.14 However, the authors report that bone marrow involvement in UP patients does not appear to correlate with the clinical symptoms of mast cell activation and therefore they express doubts as to whether bone marrow biopsies are useful to decide on further medical treatment. We believe that knowledge of bone marrow involvement is important for two reasons. The first is that one may anticipate very severe anaphylactic reactions in these patients. This fact is relevant for immunotherapy as well as in respect of situations involving a risk for mast cell degranulation, such as after the administration of certain drugs.15 Secondly, patients with a c-KIT mutation are subject to the risk of disease progression and are likely to develop more aggressive forms of disease that need periodic follow-up investigations.15,16 Three of our patients with skin involvement had © 2014 The Australasian College of Dermatologists
6
E Aberer et al.
a c-KIT gene mutation and were candidates for regular monitoring. On the other hand, Escribano and colleagues reported that indolent SM in adults is associated with a low rate of disease progression rate, and the large majority of these patients have a normal life expectancy.16 In three patients hepatomegaly or splenomegaly was noted, one in SM and two in non-mastocytosis patients; one of whom had anaphylaxis the other urticaria and angioedema. In Barete and colleagues’ large group of SM patients, half of the patients had bone involvement and osteoporosis was the most common bone manifestation (31%).17 In our 12 SM patients, one-third of the patients had bone involvement. Also in our non-mastocytosis patients osteoporosis was found in two and osteopenia in two patients (4/8 patients, 50%), which is a high number since the mean age of the patients was 20 μg/L is a minor criterion of mastocytosis, a bone marrow biopsy should also be per© 2014 The Australasian College of Dermatologists
formed. Further, these patients should be advised about their increased risk of severe anaphylactic reactions after hymenoptera bites and certain drugs.
ACKNOWLEDGEMENTS This project was sponsored by the Austrian Society of Dermatology and Venereology. We thank Marion Herzl for supplying the tryptase data.
REFERENCES 1.
2. 3.
4. 5.
6.
7. 8.
9.
10.
11.
12.
13.
14.
15.
16.
Tharp MD. Mastocytosis. In: Bolognia JL, Jorizzo JL, Rapini RP (eds). Dermatology, 2nd edn. St Louis, MO: Mosby Elsevier, 2008; 1845–53. Müller UR. Elevated baseline serum tryptase, mastocytosis and anaphylaxis. Clin. Exp. Allergy 2009; 39: 620–2. Komericki P, Arbab E, Grims R et al. Tryptase as severity marker in drug provocation tests. Int. Arch. Allergy Immunol. 2006; 140: 164–9. Caughey GH. Tryptase genetics and anaphylaxis. J. Allergy Clin. Immunol. 2006; 117: 1411–4. Ferrer M, Núñez- Cordoba JM, Luquin E et al. Serum total tryptase levels are increased in patients with active chronic urticaria. Clin. Exp. Allergy 2010; 40: 1760–6. Valent P, Akin C, Escribano L et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur. J. Clin. Invest. 2007; 37: 435–53. Amon U, Hartmann K, Horny HP et al. Mastocytosis – an update. J. Dtsch. Dermatol. Ges. 2010; 8: 695–711. Akin C, Valent P, Metcalfe D. Mast cell activation syndrome: proposed diagnostic criteria. J. Allergy Clin. Immunol. 2010; 126: 1099–104. Brockow K, Jofer C, Behrendt H et al. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy 2008; 63: 226–32. Schwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunol. Allergy Clin. North Am. 2006; 26: 451– 63. Ruëff F, Przybilla B, Bilo MB et al. Predictors of severe systematic 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. Ruëff F, Przybilla B, Biló MB 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: 105–11. de Olano DG, Caballer B, Núñez-Lopez R 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. Topar G, Staudacher C, Geisen F et al. Urticaria pigmentosa: a clinical, hematopathologic, and serologic study of 30 adults. Am. J. Clin. Pathol. 1998; 109: 279–85. Bonadonna P, Perbellini O, Passalacqua G 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. Escribano L, Alvarez-Twose I, Sánchez-Muñoz L 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.
Elevated tryptase in skin disease 17.
18. 19.
20.
Barete S, Assous N, de Gennes C et al. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann. Rheum. Dis. 2010; 69: 1838–41. Nguyen BD. CT and scintigraphy of aggressive lymphadenopathic mastocytosis. Am. J. Roentgenol. 2002; 178: 769–70. Chen CC, Andrich MP, Mican JM et al. A retrospective analysis of bone scan abnormalities in mastocytosis: correlation with disease category and prognosis. J. Nucl. Med. 1994; 35: 1471–5. Valent P, Horny HP, Triggiani M et al. Clinical and laboratory parameters of mast cell activation as basis for the formulation of diagnostic criteria. Int. Arch. Allergy Immunol. 2011; 156: 119–27. Review.
21.
22.
23.
7
Metcalfe DD. Differential diagnosis of the patient with unexplained flushing/anaphylaxis. Allergy Asthma Proc. 2000; 21: 21–4. Review. Schwartz LB, Sakai K, Bradford TR 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. Valent P, Aberer E, Beham-Schmid C 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.
© 2014 The Australasian College of Dermatologists
