Up to 5% of the adult population in the Western countries develop anaphylactic reaction to honeybee or wasp stings and reactions to stings may vary broadly from skin involvement to shock (1–3). The causes for these different reaction patterns are not completely understood. One explanation seems to be that severe anaphylactic hymenoptera sting reactions are often associated with mastocytosis, for which one diagnostic marker is elevated tryptase levels (4–8).
The protease tryptase, is expressed almost exclusively in mast cells and presents in several isoforms. Tryptase levels are a useful marker for estimating mast cell numbers and/or their activation status depending on the analyzed isoform (9). Whereas tryptase α is enzymatically inactive and released continuously, tryptase ß is secreted during mast cell degranulation (10). Tryptase γ (serine protease 31), tryptase δ (mast cell protease 7-like tryptase-3), and the brain-specific serine protease 4 (ɛ-tryptase) play no role as diagnostic measures.
Interestingly, recent studies have demonstrated that tryptase levels seem to function as an individual risk factor for increased allergic reactions even in patients without mastocytosis. Haeberli et al. (4) demonstrated increased tryptase in 7.3% of venom-allergic patients. Similar results were reported by Kucharewicz et al., (11) where increased basal serum tryptase levels were found in 11% of patients allergic to wasp or honey bee venoms. Furthermore, both studies evidenced a significant correlation of basal serum tryptase levels with sting reaction severity (4, 11).
It is known that older people are at increased risk to develop severe anaphylactic reactions after stings (12–14). The reason behind this phenomenon remains unclear. It has been speculated that elderly people suffer from a coexisting cardiovascular disease, which in the end could contribute to life-threatening anaphylaxis (3, 6). Interestingly, Kucharewicz et al. (11) found elevated serum tryptase levels with increasing age. However, the clinical significance of this finding has never been investigated closely.
In this study, we investigate the role of the basal serum tryptase as diagnostic parameter for individual risk evaluation and its impact on the severity of allergic reactions in elderly people.
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- Materials and methods
It is of great clinical importance to identify those patients at risk for developing life-threatening anaphylactic reactions (1, 3). To date, three major risk factors have been identified: (i) mastocytosis with or without elevated serum tryptase levels, (ii) elevated serum tryptase levels in patients without mastocytosis, and (iii) elderly people.
Schwartz et al. and others noticed that patients with severe anaphylactic reactions displayed higher tryptase levels even before sting challenge compared to nonreactors (11, 18–21). Ludolph-Hauser et al. (5) demonstrated the frequent occurrence of constitutively elevated tryptase levels selectively in these patients with cutaneous mastocytosis who had suffered from systemic hymenoptera sting reaction. Interestingly, tryptase levels also seem to function as an individual risk factor in nonmastocytosis patients. Recent studies have demonstrated that basal serum tryptase levels (cut-off: 11.4 μg/l) were elevated in approximately 10% of venom-allergic patients and these increased levels correlated significantly with sting reaction severity (4, 11, 22).
In this study, we found that basal serum tryptase levels (cut-off: 11.4 μg/l) were elevated in 10.9% of venom-allergic patients and this correlated significantly with sting reaction severity and age of the patients. These data are in line with reports from Kucharewicz et al. (11) showing augmented tryptase levels in 11% of allergic patients. Of interest is another study by Sturm et al. (22) In this presentation, even patients with tryptase levels between 11.4 and 6.6 μg/l also displayed an increased risk for severe sting reactions. In our study, 13 patients with tryptase levels between 11.4 and 6.6 μg/l had grade III reactions, and five patients reported of grade IV reactions. These findings suggest that even lower cut-off levels (>6.6 μg/l) of serum tryptase should be further discussed.
In our study, cutaneous or systemic mastocytosis according to the WHO guidelines could be diagnosed in just 7.5% of the patients with elevated serum tryptase level. Mastocytosis is a rare disease, seen in approximately every 1000–8000 dermatological outpatient visits (23). It is difficult to diagnose, and skin changes are often missed because of faint cutaneous manifestations (7). In our department, bone marrow biopsy was routinely offered to patients with serum tryptase levels above 15 μg/l. It is possible that in some patients with serum tryptase levels between 11.4 and 15 μg/l, systemic involvement may have been overlooked. These patients might be underdiagnosed with `indolent mastocytosis’. Anyway, serum tryptase can be in normal ranges in patients with mastocytosis, and serum tryptase and even bone marrow biopsy without pathological findings do not exclude mastocytosis (24). Our findings are in line with other reports showing that elevated tryptase concentrations correlate with sting severity, however, without obligatory finding of mastocytosis in those patients (11).
The causes for constitutively raised tryptase concentrations in certain patients are not clear. Other reasons beside mastocytosis could be acute myelocytic leukemia, various myelodysplastic syndromes, hypereosinophilic syndrome associated with the FLP1L1-PDGFRA mutation, end-stage renal failure, and treatment of onchocerciasis (25).
It has been known for a long time that elderly people suffer from increased severity of sting reactions (3, 12, 13). The reason behind this phenomenon remains unclear, though an imbalanced cardiovascular system in those patients has been brought under suspicion (6).
Our data identify increased serum tryptase levels in elderly people as an individual risk factor for severe allergic sting reaction. We could evidence a significant increase in serum tryptase with increasing age, and these elevated levels correlate significantly with the severity of sting reactions. Thus, we could identify serum tryptase as a key factor for the risk assessment especially in elderly people. Underlying causes for these increased basal serum tryptase levels in elderly people could be, at least partially, responsible for increased severity of allergic reaction observed in those patients. Clarification of the mechanisms, which lead to these increased serum tryptase levels in elderly, needs further investigation. To this end, it could be postulated that various myelodysplastic syndromes that are often overlooked at start could play a role especially in elderly patients and should therefore receive special consideration.
However, as those patients with increased serum tryptase levels are beyond doubt at increased risk for life-threatening anaphylactic reactions, we propose that especially elderly patients with increased tryptase levels should be treated with increased venom doses during immunotherapy, and a life-long continuation may also be considered as recommended for mastocytosis patients with mastocytosis (26).