Elevated Tryptase Research Articles

M353 AN INNOVATIVE TREATMENT APPROACH TO HEREDITARY ALPHA-TRYPTASEMIA AND INTERSTITIAL CYSTITIS

Hereditary alpha-tryptasemia (HAT) is an autosomal dominant disorder characterized by excess copies of the alpha-tryptase gene TPSAB1. There is elevated baseline tryptase and associated symptoms, including flushing, hives, irritable bowel syndrome and dysautonomia. We describe a patient with HAT and interstitial cystitis (IC) in whom bladder-directed therapy was effective in treating systemic symptoms.

1240 Increased Mucosal Innate Immune Activation in Hereditary Alpha Trytpasemia Subjects Is Predictive of Clinical Response to Tofacitanib Therapy

INTRODUCTION: Hereditary alpha hypertryptasemia (HAT) is a genetic disorder associated with elevated serum tryptase as well as GI symptoms including nausea, vomiting, heartburn, abdominal pain, and diarrhea. HAT subjects are often mis-diagnosed with gastroparesis or IBS. HAT is estimated to impact up 6% of Caucasians in the US (Nat Genet. 2016 Dec;48(12):1564-1569.). Elevated tryptase in HAT is not associated with clonal mast cell (MC) disease, but does cause MC activation. MCs and memory T cells are increased in the HAT small intestine. The mechanism whereby tryptase produces clinical symptoms is unknown. We hypothesize that tryptase expression results in an intestinal epithelial cell (IEC) innate immune activation called pyroptosis. Tofacitanib is a JAK-STAT inhibitor which is believed to reduce innate immune activation. The aim of this pilot study was to evaluate the level of pyroptosis in HAT patients who have no endoscopic or histologic evidence of inflammation and determine its predictive value for clinical response to tofacitanib. METHODS: HAT was confirmed by genetic testing in all subjects. All subjects had undergone a colonoscopy and had available small bowel biopsies. Biopsy samples were blindly analyzed for pyroptosis using the Maximus Biological assay kit. Samples with at least 10 villi were analyzed for IEC pyroptosis. Subjects' clinical response to therapy was analyzed, stratified by pre-treatment biopsy pyroptosis levels and type of therapy. RESULTS: 11 patients (2 M, 9 F) with an average age of 50 were included. All subjects had confirmed duplication or triplication in their TPSAB1 gene. The average tryptase was 18.5 mcg/L (<8.5 mcg/L) and the average number of mast cells per HPF by CD117 exceeded 52.4 per HPF (nml small bowel is < 25/hpf). All subjects reported nausea, vomiting, abdominal pain and diarrhea symptoms. Ileal biopsy pyroptosis reveled a three-fold increase in mucosal innate immune activation, an average of 33 ± 10 positive cells/1000 IECs (normal is up to 10/1000 IEC). Only one HAT subject who was on adalimumab therapy at the time of biopsy had a normal pyroptosis level. Three of the patients in this cohort received treatment with tofacitinib who responded all had elevated pyroptosis levels (22 ± 2.9 positive cells/1000 IECs). Tryptase levels were reduced by 25% to 50% with a dramatic improvement in their GI symptoms. CONCLUSION: Mucosal innate immune activation is evident in HAT subjects and can predict response to tofacitinib therapy.

Tryptase values in anaphylaxis and insect allergy.

To recognize the relevance of serum tryptase measurement as a useful tool for the diagnosis of allergic diseases and mast cell disorders. Recent data on the role of mast cells and tryptase in allergic and other diseases provide new understanding into the mechanisms and causes of anaphylaxis. Measurement of transiently elevated tryptase levels shortly after a severe reaction can help elucidate mechanism behind the reaction in identifying mast cell activation. Hymenoptera venom allergy represents an important cause of morbidity and mortality worldwide. Venom allergy is a typical IgE-mediated reaction because of sensitization to one or more allergens of the venom, and accounts for 1.5-34% of all cases of anaphylaxis. There is a preferential association between insect venom allergy and mastocytosis. The diagnosis of a clonal mast cell disease leads to therapeutic consequences concerning the treatment of venom allergy. In conclusion, baseline tryptase levels support the clinical diagnosis of anaphylaxis and mast cell disorders, determine venom immunotherapy treatment and are relevant in deciding on lifelong treatment.

Risk factors and indicators of severe systemic insect sting reactions.

Hymenoptera venom allergy ranks among the top three causes of anaphylaxis worldwide, and approximately one-quarter of sting-induced reactions are classified as severe. Fatal sting reactions are exceedingly rare, but certain factors may entail a considerably higher risk. Delayed administration of epinephrine and upright posture are situational risk factors which may determine an unfavorable outcome of the acute anaphylactic episode and should be addressed during individual patient education. Systemic mastocytosis and senior age are major, unmodifiable long-term risk factors and thus reinforce the indication for venom immunotherapy. Vespid venom allergy and male sex likewise augment the risk of severe or even fatal reactions. Further studies are required to assess the impact of specific cardiovascular comorbidities. Available data regarding potential effects of beta-blockers and/or ACE inhibitors in coexisting venom allergy are inconclusive and do not justify recommendations to discontinue guideline-directed antihypertensive treatment. The absence of urticaria/angioedema during sting-induced anaphylaxis is indicative of a severe reaction, serum tryptase elevation, and mast cell clonality. Determination of basal serum tryptase levels is an established diagnostic tool for risk assessment in Hymenoptera venom-allergic patients. Measurement of platelet-activating factor acetylhydrolase activity represents a complementary approach but is not available for routine diagnostic use.

MON-508 Misdiagnosed Bone Metastasis: A Rare Case of Polyostotic Bone Lesions

Background The most common cause of diffuse bone lesions in adults is metastatic disease. We present a case of a rare cause of polyostotic bone disease associated with low bone mineral density in a postmenopausal woman. Case description 53-year-old female presented with back pain. She had no significant past medical history besides a chronic rash on her back and chest that was triggered by direct sunlight. She denied flushing, diarrhea or syncope. On exam, she had tenderness in the lumbar spine and dermatographism. Plain radiographs revealed multiple sclerotic lesions in the ribs, lumbar spine and pelvis, and notably a 2.5cm lesion at L5 vertebral body concerning for metastatic disease. Her blood cell counts, liver enzymes, glomerular filtration rate, lactate dehydrogenase, alkaline phosphatase, PTH intact, Phosphorus, Calcium and vitamin D were within normal limits. Serum and urine protein electrophoresis did not show monoclonal gammopathy. Serum tryptase level was elevated at 57 ng/mL (<11ng/mL). Bone marrow biopsy revealed multiple aggregates of atypical spindled mast cells that showed aberrant expression of CD25. KIT point mutation at codon 816 was identified. Systemic Mastocytosis (SM) was diagnosed. This was considered indolent variant due to lack of organopathy or dysmyelopoiesis. Initiation of histamine receptor blockers led to improvement of symptoms. Initial bone density scan interpretation was challenging due to mastocyte infiltration in regions of interest. The only regions not affected were L1 and the left femoral neck. Osteoporosis was diagnosed due to a T-score under -2.5 at these sites. The patient was less than one year post-menopause and likely at the peak of her bone loss. She was started on alendronate. Discussion The skeleton is one of the most frequent sites of involvement in SM. Patients can present with diffuse bone pain or pathologic fractures leading to imaging studies that reveal both osteolytic and osteosclerotic lesions. Widespread metastatic disease may be initially misdiagnosed, such as in our patient, leading to medical errors. SM can be identified by an elevated tryptase level and confirmed with bone marrow biopsy. Mast cells can exert a direct stimulatory effect on osteoblast and osteoclasts. The predominance of either process would direct bone involvement towards bone sclerosis or bone loss. There is a high prevalence of fractures and osteoporosis in SM. Available studies identify osteoporosis prevalence around 18-37%. Whether patients with focal or diffuse osteosclerosis have more or less osteoporosis or risk of fractures has not been determined due to absence of large longitudinal studies. DXA diagnosis of osteoporosis may be inaccurate due to patchy distribution of mastocyte cell infiltrates or presence of fractures. Small studies on the effect of bisphosphonates have been published with evidence of greater BMD gain with zoledronic acid.

Inflammatory reaction patterns of the lung as a response to alveolar hypoxia and their significance for the diagnosis of asphyxiation

Providing evidence of asphyxia death is a challenging issue in forensic pathology. Besides helpful macroscopical signs (e.g. strangulation mark, lung edema), recent data from literature indicate that the time of protracted asphyxia suffices to trigger an increase of giant cells and a migration of inflammatory cells from the bone marrow to the lung, thus offering a help in diagnosis of asphyxia death. In search of new valid asphyxia markers, the present study examined this hypothesis and investigated the leading role of pre-existing lung tissue cells and their functional state in reaction patterns to asphyxia. In specimens of suffocated human lungs following a short (n = 13) and a long asphyxia terminal episode (n = 15), and controls (sudden cardiovascular (n = 11) and traumatic deaths (n = 7)), the count of alveolar phagocytes, megakaryocytes, giant and mast cells, using H&E and toluidine blue staining, was performed. To show macrophage activation, immunohistochemical stainings for CD68, late (25F9) and early (MRP-8/-14) stage inflammatory markers were used. Measuring concentration of tryptase in femoral blood acted as a parameter for mast cell degranulation and consequently their activation. Results showed the lack of specificity of macroscopical parameters despite an association of suffocation with heavy lung edema. No significant differences in the numbers of inflammatory cells in the lungs of different case groups were detected. The doubling of MRP-8- and a five-fold elevation of MRP-14-positive cells compared to cardiovascular controls, proved an early activation state of pre-exiting monocytes in protracted asphyxia. These activated monocytes induced the degranulation of mast cells, resulting in slightly elevated tryptase levels in suffocation compared to cardiovascular controls. In summary, the duration of asphyxia (max. 20 min in cases investigated) only suffices to cause changes on molecular level, being not detectable in any specific macroscopical or histological form in the lung. Despite a potential utility of this molecular insight in individual cases, these results point to the classic doctrine of the evaluation of a rounded overall picture, accentuating on the proof of the ligature tool and the marks of suffocation process.

Elevated tryptase during aspirin desensitization in aspirin-exacerbated respiratory disease

Elevated tryptase during aspirin desensitization in aspirin-exacerbated respiratory disease

A CASE REPORT OF HEREDITARY ALPHA-TRYPTASEMIA SUCCESSFULLY TREATED WITH OMALIZUMAB

Introduction Hereditary alpha-tryptasemia is a disorder with elevated tryptase associated with increased copy numbers in the TPSAB1 gene. Patients can have various symptoms ranging from flushing, pruritis, autonomic dysfunction, GI dysmotility to even anaphylaxis. We report a case of a 10-year old female who had clinical improvement with omalizumab treatment, which we believe is the first reported case of successful use of omalizumab in this condition. Case Description We report a 10-year old female who at age 7 presented with episodes of idiopathic anaphylaxis, urticaria, flushing, dysautonomia and abdominal pain. Baseline tryptase levels fluctuated between 16-21 ng/mL. Bone marrow biopsy confirmed non-clonal mast cell disease. She underwent genetic testing at NIH and was found to have a triplication of the TPSAB1 gene, which confirmed the diagnosis of heredity alpha-tryptasemia. Prior to her presentation at our institution, she was on a regimen of cetirizine, ranitidine, cromolyn, and odansetron with inadequate symptom control. Ketotifen therapy was initiated with improvement of her GI/flushing symptoms, but she had persistent episodes of anaphylaxis with frequent epinephrine usage and ER visits. Omalizumab 300mg monthly was initiated with significant improvement of her symptoms, including no further episodes of anaphylaxis. A recent trial off of omalizuamb resulted in worsening urticaria and flushing and, once re-initiated, symptoms again became controlled. Discussion To our knowledge, this is the first reported case of a patient with hereditary alpha-tryptasemia treated with omlizumab. Omalizumab can be considered for adjunct therapy for heredity alpha-tryptasemia if antihistamines and mast cell stabilizers provide inadequate symptom control of their mast cell-related symptoms. Hereditary alpha-tryptasemia is a disorder with elevated tryptase associated with increased copy numbers in the TPSAB1 gene. Patients can have various symptoms ranging from flushing, pruritis, autonomic dysfunction, GI dysmotility to even anaphylaxis. We report a case of a 10-year old female who had clinical improvement with omalizumab treatment, which we believe is the first reported case of successful use of omalizumab in this condition. We report a 10-year old female who at age 7 presented with episodes of idiopathic anaphylaxis, urticaria, flushing, dysautonomia and abdominal pain. Baseline tryptase levels fluctuated between 16-21 ng/mL. Bone marrow biopsy confirmed non-clonal mast cell disease. She underwent genetic testing at NIH and was found to have a triplication of the TPSAB1 gene, which confirmed the diagnosis of heredity alpha-tryptasemia. Prior to her presentation at our institution, she was on a regimen of cetirizine, ranitidine, cromolyn, and odansetron with inadequate symptom control. Ketotifen therapy was initiated with improvement of her GI/flushing symptoms, but she had persistent episodes of anaphylaxis with frequent epinephrine usage and ER visits. Omalizumab 300mg monthly was initiated with significant improvement of her symptoms, including no further episodes of anaphylaxis. A recent trial off of omalizuamb resulted in worsening urticaria and flushing and, once re-initiated, symptoms again became controlled. To our knowledge, this is the first reported case of a patient with hereditary alpha-tryptasemia treated with omlizumab. Omalizumab can be considered for adjunct therapy for heredity alpha-tryptasemia if antihistamines and mast cell stabilizers provide inadequate symptom control of their mast cell-related symptoms.

WHAT APPEARS TO BE POSSIBLE CARCINOID IS IN FACT MAST CELL ACTIVATION SYNDROME

Introduction Mast cell activation syndrome (MCAS) has been increasingly used to define patients with episodic systemic symptoms secondary to mast cell activation that do not fit the criteria for systemic mastocytosis or monoclonal mast cell activation syndrome. Here we present a patient with MCAS with laboratory features of carcinoid syndrome. Case Description A 54-year old Caucasian female with allergic rhinitis, urticaria, flushing with and without eating, fogginess, polycythemia, and Graves disease s/p total thyroidectomy presented to establish care. Labs revealed elevated tryptase of 18 ng/mL, and an elevated 24-hour urine prostaglandin D2 of 388 ng. Bone marrow biopsy findings were normal. Serum 5-HIAA and chromogranin A were normal. However, her 24-hour urine 5-HIAA was persistently elevated. Further work up failed to reveal findings consistent with carcinoid syndrome, including negative chest and abdominal scans. Given a convincing history of venom hypersensitivity, skin tests were performed revealing positives to honeybee, wasp and mixed venom. Patient was started on oral cromolyn with improvement in her flushing symptoms. She initially experienced diarrhea and abdominal cramping which has now resolved. She has been doing well with immunotherapy for allergic rhinitis, and is currently waiting to start venom immunotherapy. Discussion Although our patient's work up revealed persistently elevated urine 5-HIAA consistent with carcinoid syndrome, further work up revealed a picture more consistent with mast cell disorder. This case emphasizes the importance of considering MCAS even in patients with laboratory markers seen in carcinoid syndrome. Mast cell activation syndrome (MCAS) has been increasingly used to define patients with episodic systemic symptoms secondary to mast cell activation that do not fit the criteria for systemic mastocytosis or monoclonal mast cell activation syndrome. Here we present a patient with MCAS with laboratory features of carcinoid syndrome. A 54-year old Caucasian female with allergic rhinitis, urticaria, flushing with and without eating, fogginess, polycythemia, and Graves disease s/p total thyroidectomy presented to establish care. Labs revealed elevated tryptase of 18 ng/mL, and an elevated 24-hour urine prostaglandin D2 of 388 ng. Bone marrow biopsy findings were normal. Serum 5-HIAA and chromogranin A were normal. However, her 24-hour urine 5-HIAA was persistently elevated. Further work up failed to reveal findings consistent with carcinoid syndrome, including negative chest and abdominal scans. Given a convincing history of venom hypersensitivity, skin tests were performed revealing positives to honeybee, wasp and mixed venom. Patient was started on oral cromolyn with improvement in her flushing symptoms. She initially experienced diarrhea and abdominal cramping which has now resolved. She has been doing well with immunotherapy for allergic rhinitis, and is currently waiting to start venom immunotherapy. Although our patient's work up revealed persistently elevated urine 5-HIAA consistent with carcinoid syndrome, further work up revealed a picture more consistent with mast cell disorder. This case emphasizes the importance of considering MCAS even in patients with laboratory markers seen in carcinoid syndrome.

Improvement of the Elevated Tryptase Criterion to Discriminate IgE- From Non-IgE-Mediated Allergic Reactions: Erratum.

Improvement of the Elevated Tryptase Criterion to Discriminate IgE- From Non-IgE-Mediated Allergic Reactions: Erratum.

CATAMENIAL ANAPHYLAXIS PRESENTING PRIOR TO ONSET OF MENSES

Introduction Catamenial anaphylaxis is an uncommon, heterogeneous disorder related to type 1 hypersensitivity to endogenous progesterone. We report a twelve-year old premenstrual female who presented with recurrent episodes of anaphylaxis with improvement after starting an oral contraceptive. Case Description A twelve-year old female presented with six episodes of anaphylaxis that occurred monthly. Her symptoms included nausea, vomiting, diarrhea, urticaria, dizziness, and facial angioedema all requiring hospitalization. She was treated with intramuscular epinephrine, antihistamines, and systemic steroids. Her third episode occurred thirty-six hours after she had received her first dose of omalizumab. Her symptoms were uncontrolled despite treatment with prednisone, cromolyn, ketotifen, anti-leukotrienes and antihistamines. Her work-up for anaphylactic triggers, systemic mastocytosis, and carcinoid syndrome was negative. Her lab-work showed an elevated tryptase to 13.2 ug/L from a baseline of 2.0 ug/L. There was concern for catamenial anaphylaxis given the cyclical nature of her symptoms, however the patient had not started menstruation. She underwent an oral challenge with progesterone with no reaction. She was started on low-ogestrel and did not have any subsequent episodes of anaphylaxis. Discussion Catamenial anaphylaxis is described as recurrent episodes of multi-system allergic reactions occurring around the time of menstruation. This case is the first description of a premenstrual female who presented with catamenial anaphylaxis. The patient had no further episodes of anaphylaxis following initiation of an oral contraceptive as opposed to previous therapies. It is important to consider catamenial anaphylaxis in the differential diagnosis of idiopathic anaphylaxis prior to the onset of menses.

Plasma tryptase elevation during aspirin-induced reactions in aspirin-exacerbated respiratory disease

Plasma tryptase elevation during aspirin-induced respiratory reactions occurs in 50% of reactions despite CysLT1R antagonist prophylaxis and identifies lung function decline and extra-respiratory symptoms in aspirin-exacerbated respiratory disease (AERD).

Neuromuscular blocking agents induced anaphylaxis: Results and trends of a French pharmacovigilance survey from 2000 to 2012

Perioperative anaphylaxis mainly involves neuromuscular blocking agents (NMBAs) with an IgE-mediated mechanism. In France, this life-threatening condition is reported by anesthetists and allergologists, and two safety alerts concerning suxamethonium were raised in 2011 and 2012. This led to start a national survey over the 2000-2012 period which objectives were to provide a descriptive analysis, to estimate incidence rates, and to analyze the trends over this period. The French pharmacovigilance database was retrospectively queried for all the available NMBAs. Anaphylaxis cases with elevated tryptase and positive skin tests were qualified as "confirmed cases." Subgroup analysis compared atracurium and cisatracurium vs suxamethonium and rocuronium. A total of 680 confirmed cases and 944 nonconfirmed cases were identified. Suxamethonium was the most implied NMBA (64%). Incidence rates (according to sales data) of suxamethonium and rocuronium were, respectively, 10- and 13-folds higher than those of the others NMBAs, regardless the confirmed/nonconfirmed status. Cisatracurium incidence rates remained stable over the period, while suxamethonium and atracurium increased and rocuronium first decreased but re-increased after 2006. Male patients were more frequent in the subgroup "atracurium-cisatracurium" (P=.019), whereas obesity and emergency setting were more frequent in the subgroup "rocuronium-suxamethonium." Shared characteristics were the poorly documented previous exposure to NMBA(s) and an insufficient adherence of patients to perform skin tests, showing the need to improve this procedure. Suxamethonium and rocuronium are markedly more involved in perioperative anaphylaxis than the other available NMBAs. Patients should be more informed about their perioperative anaphylaxis and its consequences.

Elevated Tryptase in EoE Is an Independent Phenomenon Associated with Extra-Esophageal Symptoms.

Eosinophilic esophagitis (EoE) is a chronic disease characterized histologically by > 15 eosinophilsper high-power field (eos/hpf). Esophageal mucosal mast cells have been implicated in EoE pathogenesis. The association of atopy with EoE has been established but has not been correlated with levels of serum tryptase. The lack of concurrent atopy in some patients suggests the possibility that atopy may either be the related subtype of EoE or may be a sign of comorbidities. No study has looked at whether patients present with different phenotypes/comorbid disease when they have evidence of elevated serum tryptase. We hypothesized that these patients differ with respect to presentation and comorbidities with more refractory GI disease. To examine whether elevations of serum tryptase associate with different, more severe clinical presentations in EoE patients which may be explained via mast cell activation. Retrospective chart review identified 72 patients with EoE with results for serum tryptase between 2015 and 2016. Patients were classified as TryptaseHI (tryptase > 10.9µg/l) and TryptaseLO (< 10.9µg/l). Clinical characteristics and treatment response were compared using univariate analysis and multivariate regression between the groups. Out of 72 patients, 12 were tested as TryptaseHI (16.7%, 95% CI 8.1-25.3%). TryptaseHI was associated frequently with asthma (P = 0.0003), urticaria (P = 0.002), arthralgia (P = 0.005), sinusitis (P = 0.03), nausea/vomiting (P = 0.046), and eosinophilic gastrointestinal disease (P = 0.001). Asthma and arthralgia were found to be significantly associated with TryptaseHI (P = 0.0013, P = 0.0098, respectively). Mucosal eosinophil counts and tryptase levels were not correlated (R2 0.095, P = 0.77). Tryptase did not resolve with resolution of esophageal eosinophilia. We found that EoE patients with elevated tryptase levels more commonly presented with asthma, urticaria, arthralgia, nausea/vomiting, sinusitis, and more distal eosinophilia. This indicates that atopy in EoE patients warrants further exploration. The lack of correlation between histologic remission and reduction of serum tryptase levels post-treatment suggests that mast cell activation may be an independent, yet associated disease. More study into this unique association is warranted.

Harlequin syndrome in a subject with multinodular goiter and an elevated tryptase levels

Harlequin syndrome in a subject with multinodular goiter and an elevated tryptase levels

Improvement of the Elevated Tryptase Criterion to Discriminate IgE- From Non-IgE-Mediated Allergic Reactions.

Differentiating between immunoglobulin E (IgE)-dependent and IgE-independent hypersensitivity reactions may improve the etiologic orientation and clinical management of patients with allergic reactions in the anesthesia setting. Serum tryptase levels may be useful to discriminate the immune mechanism of allergic reactions, but the diagnostic accuracy and optimal cutpoint remain unclear.We aimed to compare the diagnostic accuracy of tryptase during reaction (TDR) alone and the TDR/basal tryptase (TDR/BT) ratio for discriminating IgE- from non-IgE-mediated allergic reactions, and to estimate the best cut point for these indicators. We included 111 patients (45% men; aged 3-99 years) who had experienced an allergic reaction, even though the allergic reaction could be nonanaphylactic. Allergy tests were performed to classify the reaction as an IgE- or non-IgE-mediated one. The area under the curve (AUC) of the receiver operating characteristic analysis was performed to estimate the discriminative ability of TDR and TDR/BT ratio. An IgE-mediated reaction was diagnosed in 49.5% of patients, and 56% of patients met anaphylaxis criteria. The median (quartiles) TDR for the IgE-mediated reactions was 8.0 (4.9-19.6) and 5.1 (3.5-8.1) for the non-IgE-mediated (P = .022). The median (quartiles) TDR/BT ratio was 2.7 (1.7-4.5) in IgE-mediated and 1.1 (1.0-1.6) in non-IgE-mediated reactions (P < .001). The TDR/BT ratio showed the greatest ability to discriminate IgE- from non-IgE-mediated reactions compared to TDR (AUC TDR/BT = 0.79 [95% confidence interval (CI), 0.70-0.88] and AUC TDR = 0.66 [95% CI, 0.56-0.76]; P = .001). The optimal cut point for TDR/BT (maximization of the sum of the sensitivity and specificity) was 1.66 (95% CI, 1.1-2.2). The TDR/BT ratio showed a significantly better discriminative ability than TDR to discriminate IgE- from non-IgE-mediated allergic reactions. An optimal TDR/BT ratio threshold of approximately 1.66 may be useful in clinical practice to classify allergic reactions as IgE- or non-IgE-mediated.

Diagnostic role of serum tryptase in anaphylactic deaths in forensic medicine: a systematic review and meta-analysis.

Postmortem diagnosis of sudden death due to anaphylaxis can be very difficult due to the non-specific pathological findings in forensic practice. Postmortem serum tryptase has been used as an indicator of possible ante-mortem anaphylaxis. Though many previous studies have been conducted to explore the diagnostic significance of serum tryptase for lethal anaphylaxis, inconsistent results were documented. In this study, we made a retrospective study and presented a systematic review and meta-analysis that aims to summarize the diagnostic significance of postmortem serum tryptase in the deceased with and without anaphylactic shock and to calculate a cutoff value for future reference in the identification of deaths due to anaphylactic shock. A complete literature search in the PubMed, Cochrane Library, CNKI and Embase databases (published prior to March 1st, 2017) was performed. The quality of the eligible literature was evaluated according to the Newcastle-Ottawa Quality Assessment Scale (NOS), and the relevant data was extracted. The procedure of meta-analysis was performed by RevMan 5.3 software. Subgroup analysis was performed according to different causes of death. A total of nine studies with 296 patients were identified. The NOS of each included study was equal to 7. The results indicated that high concentrations of tryptase were significantly associated with anaphylactic shock when compared to the other causes of death. The weighted mean difference (WMD) was 29.53 (95% CI = 7.58-51.47, p = 0.008). Similar results were detected in the subgroup analysis when compared to deaths due to cardiovascular disease (CVD). However, no obvious elevation of tryptase in decedents with CVD compared to the other cause of death was observed (WMD = 4.42, 95% CI = -0.94-9.79). We concluded that high serum tryptase is a promising diagnostic biomarker for deaths due to anaphylactic shock, especially when it is higher than 30.4μg/L.

Pediatric Mast Cell Activation Syndrome

Patients with mast cell activation syndrome(MCAS) have symptoms consistent with mast cell mediator release, elevation of mast cell(MC) mediator(s) and symptomatic resolution following medications that block MC mediator effect(s). MC mediator levels in pediatric mast cell disorders are unknown. Our hypothesis is that the pattern of mast cell mediator(s) elevation in pediatric MCAS resembles adult MCAS. A retrospective chart review of 104 children who underwent evaluation for MCAS (2015-2017) was performed. Levels of serum tryptase, urinary n-methyl-histamine(n-MH), 2,3-dinor11β-prostaglandin-F2α(PG-D2), and leukotriene E4(LTE4) are reported. Thirty-two patients had ≥1 elevated urine MC mediators, based on established adult reference intervals. Of this total, 1 patient had systemic mastocytosis, 4 patients had cutaneous mastocytosis, and 6(6%) patients had MCAS. The average age at diagnosis was 9±5years. Serial testing in two patients with normal baseline revealed an elevated urine mast cell mediator level during an episode; one of those patients (with suspected familial hypertryptasemia) had PG-D2 elevation and the other LTE4 elevation. Five patients (83%) had at least 2 elevated MC mediators. More patients had an elevated PG-D2 (n=5) compared to serum tryptase(n=2). There was a greater percentage of patients that had elevated PG-D2 compared to an elevated serum tryptase for flushing(80-vs-50%), diarrhea(100-vs-100%), and abdominal pain(100%-vs-50%). There was a greater percentage of patients with elevated tryptase compared PG-D2 for pruritus(100-vs-60%) and urticaria(50-vs-40%). Urinary PG-D2 is the most frequently elevated product in our pediatric MCAS cohort, resembling adult MCAS. We recommend measurement of all MC mediators in patients with symptoms suggestive of MCAS.

Mast cells and cancer.

Mast cells (MCs) are a potent proangiogenic factor in tumors, they product several pro-angiogenic factors such as fibroblast growth factor 2 (FGF-2), vascular epithelial growth factor (VEGF), tryptase and chymase. Tryptase is a serine protease classified as α-tryptase and β-tryptase, both produced by MCs. Tryptase degrades the tissues, playing an important role in angiogenesis and in the development of metastases. Serum tryptase increases with age, with increased damage to cells and risk of developing a malignancy and it could be considered the expression of a fundamental role of MCs in tumor growth or, on the contrary, in the antitumor response. Many biomarkers have been developed in clinical practice for improving diagnosis and prognosis of some neoplasms. Elevated tryptase levels are found in subgroups of patients with haematologic and solid cancers. In the current review, we want to update the perspectives of tryptase as a potential biomarker in daily practice in different neoplasms.

Persistent tryptase elevation in a patient with Gaucher disease

Persistent tryptase elevation in a patient with Gaucher disease