Clinical and Laboratory Profile of Patients With Anaphylaxis to Fire Ant Venom (Solenopsis Sp) Under Specific Subcutaneous Immunotherapy.

Anaphylaxis to fire ant venoms (Solenopsis sp) is a significant cause of systemic allergic reaction caused by Hymenoptera stings in children. There are only a few reports about the safety and efficacy of specific immunotherapy. We aim evaluate clinical characteristics, IgE and IgG4 specific responses of patients undergoing immunotherapy with a whole-body extract of Solenopsis sp after one year of the maintenance phase. Thirty-three patients were enrolled due to anaphylaxis by fire ant venom (Solenopsis sp) and underwent specific venom immunotherapy. They were assessed at baseline and one year after the beginning of the maintenance phase for skin test; specific IgE and IgG4 antibodies to fire ant venom; tryptase. All patients included presented a severe anaphylactic reaction. Although two patients (6.25%) presented a tryptase level higher than 11.4 ug/ml, systemic mastocytosis was ruled out. There was no relationship between the severity of the reaction with gender, tryptase level, atopy, previous reactions, concentration of the allergen in the skin test or specific IgE level. There was an increase of the specific IgG4/IgE ratio between the two time points. Reactions were local, with only two mild systemic reactions during the build-up phase. Twenty patients had accidental stings during immunotherapy, with 3 presenting only urticaria. This study is unprecedented in evaluating clinical and laboratory data in the fire ant immunotherapy. Our results show that after one year of the maintenance phase, patients did not develop any severe reaction with only a few mild reactions and presented a significant production of specific IgG4.

Mast cells and tryptase. Modern aspects

The present review considers the role of mast cells (MC) and tryptase levels in various pathological conditions in children and adults. The main causes of hypertryptasemia are presented, as well as a list of the most important stimuli that can cause activation of MC. Cliical allergologists should focus their clinical practice on the patients with anaphylaxia and suspected MC activation syndromes. Moreover, hypertryptasemia (> 20 ng/ml) is considered an additional diagnostic criterion for systemic mastocytosis, according to the WHO recommendations. As a rule, the level of tryptase is constantly elevated in most patients with systemic mastocytosis, whereas it is undergo changes in acute IgE-mediated hypersensitivity reactions. In cases of anaphylaxia, tryptase concentration should be determined in the patients during the first hours following onset of acute allergic reaction, and 24-48 hours later. Recommendations are given for determining tryptase levels in blood serum of the patients (basal and peak values), and algorithms are provided for usage of these indexes in various diseases. The article also provides the assessed threshold values of tryptase when diagnosing anaphylaxia, MC activation syndromes, and a novel disorder – alpha-tryptasemia. In the diagnosis of hereditary alpha-tryptasemia, as well as MC activation syndromes (primary and secondary), clinical manifestations in the patient and time dynamics of tryptase levels should be taken into account. The accumulated experience allowed to consider, first of all, frequency of severe allergic reactions (most often as anaphylaxia) in the patients with suspected MC activation syndromes. The syndrome of MC activation is characterized by excessive release of their granule contents without signs of clonal proliferation, which in many cases may be due to gene allele duplication, especially, TPSAB1 α-tryptase gene. For patients with hereditary alpha-tryptasemia, the most characteristic manifestations are represented by vegetative-vascular dystonia (orthostatic tachycardia), joint hypermobility, etc. Hence, determination of tryptase level (especially in time course) should be given more attention in the practice of clinicians. Difficulties with interpretation of the results arise in cases when tryptase concentration remains within normal range (up to 11.4 ng/ml), and the patient has clinically evident mastocytosis, or MC activation syndromes. If the patient has a history of anaphylaxia, especially after bites of hymenoptera insects, the TC activation syndromes should be excluded.

Case Report: Evolution of KIT D816V-Positive Systemic Mastocytosis to Myeloid Neoplasm With PDGFRA Rearrangement Responsive to Imatinib

Systemic mastocytosis (SM) is a rare neoplasm resulting from extracutaneous infiltration of clonal mast cells (MC). The clinical features of SM are very heterogenous and treatment should be highly individualized. Up to 40% of all SM cases can be associated with another hematological neoplasm, most frequently myeloproliferative neoplasms. Here, we present a patient with indolent SM who subsequently developed a myeloid neoplasm with PDGFRA rearrangement with complete response to low-dose imatinib. The 63-year-old patient presented with eosinophilia and elevated serum tryptase level. Bone marrow analysis revealed aberrant MCs in aggregates co-expressing CD2/CD25 and KIT D816V mutation (0.01%), and the FIP1L1-PDGFRA fusion gene was not identified. In the absence of ‘B’ and ‘C’ findings, we diagnosed an indolent form of SM. For 2 years after the diagnosis, the absolute eosinophil count progressively increased. Bone marrow evaluation showed myeloid hyperplasia and the FIP1L1-PDGFRA fusion gene was detected. Thus, the diagnosis of myeloid neoplasm with PDGFRA rearrangement was established. The patient was treated with imatinib 100 mg daily and rapidly obtained a complete molecular remission. The clinical, biological, and therapeutic aspects of SM might be challenging, especially when another associated hematological disease is diagnosed. Little is known about the underlying molecular and immunological mechanisms that can promote one entity prevailing over the other one. Currently, the preferred concept of SM pathogenesis is a multimutated neoplasm in which KIT mutations represent a “phenotype modifier” toward SM. Our patient showed an evolution from KIT mutated indolent SM to a myeloid neoplasm with PDGFRA rearrangement; when the eosinophilic component expanded, a regression of the MC counterpart was observed. In conclusion, extensive clinical monitoring associated with molecular testing is essential to better define these rare diseases and consequently their prognosis and treatment.

Cladribine Therapy for Advanced and Indolent Systemic Mastocytosis: Mayo Clinic Experience in 42 Consecutive Cases

Background Systemic mastocytosis (SM) is formally classified as advanced, smoldering (SSM), or indolent (ISM). Advanced SM indicates the presence of an associated non-mast cell lineage hematologic neoplasm (SM-AHN) or at least one "C finding" (i.e. features of organopathy from mast cell infiltration); the latter defines aggressive SM (ASM). Both advanced SM and ISM might be associated with MC mediator symptoms (MC-MSs) or urticaria pigmentosa (UP). Current drug therapy for SM is primarily directed at reversing C findings or alleviating symptoms/UP, and includes cladribine, midostaurin, and avapritinib. The former has a long track-record of safety while the latter two are recent additions that target the associated KIT mutation, but with concerning gastrointestinal and neurological side effects. We retrospectively reviewed our experience with cladribine therapy in SM, in order to maintain a proper perspective in making treatment choices. Methods The current study includes 42 patients with SM (22 advanced and 20 indolent/smoldering), recruited from the Mayo Clinic SM database, based on documentation of treatment with cladribine. Conventional criteria were used for diagnosis and classification (Blood 2016;127:2391) and definitions of response (Eur J Clin Invest. 2007 Jun;37(6):435); in the latter regard, we utilized modified Valent criteria that incorporated a minimum of one-month duration to qualify as response. Results Advanced SM: 22 patients (median age 65 years, range 48-80; males 68%) had advanced SM, including 13 SM-AHN, 8 ASM, and 1 mast cell leukemia. Median (range) BM MC burden was 30% (10%-90%), serum tryptase 193 ng/ml (21-1370), hemoglobin 10.6 g/dL (7-15), leukocytes 6 x 10(9)/L (0.5-63), and platelets 115 x 10(9)/L (8-320). KITD816V was detected in 86% of 19 evaluated and abnormal karyotype in 14% of 21 evaluated. 50% of patients had palpable hepatomegaly, 59% palpable splenomegaly, 100% MC-MSs, and 14% UP; 87% displayed at least one C finding. Median time from BM biopsy confirmed diagnosis to initiation of cladribine therapy was 1.5 months (range 0.1-17). 55% of patients received at least 3 cycles of treatment. Overall response (OR) was documented in 17 (77%) patients with similar OR rates in ASM (88%) vs SM-AHN (69%; p=0.32), with median time to response of 3.7 months (range 0.4-9). OR included 45% major response (MR) and 32% partial response (PR). 17 patients were evaluated for BM MC response with 44% showing >50% reduction, in MCs, including 19% with complete resolution. Organomegaly response was complete in 36% and partial in 27%. Tryptase response of >50% was documented in 32%. Cladribine side effects were limited to cytopenias with 36% showing grade 3 or 4 myeloid cytopenia. Median duration of response was 6 months (range 1-67). Six patients, including 5 with SM-AHN, progressed to either AML or MCL. Among the 5 patients who did not respond to cladribine, one with ASM was successfully treated with midostaurin. Indolent or smoldering SM: 20 patients (median age 56 years, range 36-73; males 45%) had ISM (n=17) or SSM (n=3). Median (range) BM MC burden was 13% (5%-60%) and serum tryptase level 49 ng/ml (14-1630). KITD816V was detected in 95% of 19 evaluated patients and abnormal karyotype in 12% of 17 evaluated. All patients displayed MC-MSs and 46% UP. Median time from BM biopsy confirmed diagnosis to initiation of cladribine therapy was 4 months (range 0-92). 85% of patients received at least 3 cycles of cladribine therapy. OR was documented in 14 (70%) patients, including 60% complete or major regression of symptoms or UP, with median time to maximal response of 8.5 months (range 1-98); response rates in patients with UP were similar with 57% complete or major regression; 10 patients were evaluable for BM MC response with 50% showing >50% reduction in MC burden. Serum tryptase response was evaluated in 13 patients with 46% showing >50% reduction in levels. Treatment-emergent cladribine side effects were limited to cytopenias with only 3 (15%) patients experiencing grade 3 or 4 myeloid cytopenia and (n=3; 15%) and 6 (30%) experiencing grade 3 or 4 lymphopenia. Conclusions: The current study confirms the favorable side effect profile and long-term safety of cladribine as a first-line drug of choice for both indolent and advanced SM. Response to cladribine therapy was evident in all aspects of the disease, including MC-associated organopathy, UP, MC-MSs, serum tryptase level and bone marrow MC burden. Disclosures Patnaik: StemLine: Research Funding; Kura Oncology: Research Funding. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution.

Fatal anaphylaxis due to peanut exposure from oral intercourse

Background Intimacy-related allergic reactions, including anaphylaxis, are under-reported due to social stigma, lack of awareness, and misdiagnosis. The differential diagnosis for intimacy-related anaphylaxis is extensive and includes systemic human seminal plasma allergy, exercise-induced anaphylaxis, asthma exacerbation, latex allergy, and transference of food or drug allergens through saliva or seminal fluid. Case presentation Two adolescents met on a popular dating phone application. One individual had a long-standing history of asthma and peanut allergy. Although they never kissed, the male with peanut allergy received fellatio, while the other male had eaten peanut butter before they met. During fellatio, the peanut allergic male developed respiratory symptoms, used his bronchodilator, and collapsed. He remained unconscious despite aggressive interventions by emergency personnel called to the site. The clinical history and autopsy results suggested anaphylaxis to peanut allergen exposure from the intimate exposure as the cause of death. Discussion and conclusions To date, nearly all reported cases of intimacy-related anaphylaxis involve symptomatic women. This is the first report of intimacy-related anaphylaxis involving men who have sex with men and the first report of potential allergen transfer from oral mucosa to a patient receiving fellatio. Based on the paucity of published cases, death from intimacy-related anaphylaxis is exceedingly rare. Post-mortem analysis is inherently difficult, as an elevated tryptase level has myriad potential causes; nevertheless, the authors suggest that intimacy-related anaphylaxis due to peanut allergy is the most likely diagnosis. With increasing popularity of relationship applications, especially amongst stigmatized populations, this case highlights the importance of allergy awareness and patient education to decrease risk, particularly in the adolescent population, who are already at increased risk of severe anaphylaxis. Especially amongst those participating in intimate activities, disclosure of one’s allergies warrants discussion, as the outcome can be fatal. Our case demonstrates the crucial need for increased advocacy in food allergy, education around intimacy-related anaphylaxis, and the importance of allergy awareness and prevention across all populations.

Utility of serum tryptase in Emergency Department patients with possible anaphylaxis

BACKGROUND Diagnosing anaphylaxis is often straightforward but can be challenging if the presentation is atypical. In patients with atypical symptoms suspected to be due to an acute allergic reaction, s-tryptase can give additional diagnostic information. Measuring s-tryptase is also helpful in diagnosing mastocytosis. Obtaining s-tryptase levels has been done in the emergency department (ED) at Landspitali since 2011. The aim of this study was to evaluate the benefit of obtaining s-tryptase levels in the ED. METHODS With institutional review board approval, all cases where s-tryptase level was obtained in ED patients from 2011 – 2018 were retrospectively reviewed. A database was collected including information on patient demographics, presenting symptoms, treatment, diagnosis, s-tryptase level and follow up. RESULTS A total of 214 patients had a s-tryptase level measured. Serum tryptase was elevated (>12 µg/L) in 36 cases. Females were 131 and average age 40.6 years. Of the patients, 86.4% had skin or mucosal symptoms, 48.1% cardiovascular symptoms, 49.5% respiratory symptoms and 36.0% had gastrointestinal symptoms. An allergist reviewed 126 returning patients and 65 were considered to have had an episode of anaphylaxis. Of those 65 were 4 patients which did not meet the diagnostic criteria for anaphylaxis but had raised s-tryptase levels. Sensitivity of s-tryptase measurement was 40.9% and specificity 97.1%. CONCLUSIONS Obtaining a s-tryptase level from ED patients with possible anaphylaxis seems to be useful in atypical cases. The measurement is specific but not sensitive. No cases of mastocytosis were identified in the patient cohort.

Recent update on the management of anaphylaxis

Anaphylaxis is a life-threatening systemic allergic reaction presenting various clinical manifestations. Its prevalence has increased in almost all age groups and both sexes. Food, venom, and drugs are major causes in both children and adults; a higher prevalence of food-induced anaphylaxis is noted in children, while a higher prevalence of drug-induced anaphylaxis is noted in adults. The pathogenic mechanism is mediated by immunologic and nonimmunologic mechanisms, where mast cells and basophils are key cells that release mediators. A diagnosis of anaphylaxis is mainly based on clinical symptoms and physical findings; however, an increased serum tryptase level is a useful biomarker. Epinephrine is the first-line drug to treat acute symptoms, and an epinephrine auto-injector should be prescribed for each patient. Antihistamines and systemic corticosteroids are used to relieve symptoms. This review updates current issues in the management of anaphylaxis as well as the new guidelines for proper diagnosis and treatment.

Postmortem diagnostics of assumed suicidal food anaphylaxis in prison: a unique case of anaphylactic death due to peach ingestion

Suicidal ingestion of food which the victim is aware they are allergic to is an exceptional occurrence in the forensic field. To the best of our knowledge, no cases of suicidal food anaphylaxis have been reported to date. Therefore we present the first case described in the literature. A 30-year-old prisoner was found dead inside his cell with the remains of a peach remains next to his body, and a handwritten farewell note in his pocket. The autopsy revealed only non-specific findings, while laboratory investigations (serological, toxicological, histological, and immunohistochemical) played a pivotal role in determing the cause and manner of death. In particular, a high titer of both total and specific IgE antibodies was detected, as well as an increase of the tryptase level in cadaveric blood. Moreover, a massive concentration of salicylates was measured in the gastric contents. Microscopically, cellular residues characterized by a vegetal structure were observed in the gastric contents and elements suggestive of mast cells were detected in the glottis, lungs, and myocardium. The immunohistochemical investigation with anti-CD117 and anti-tryptase antibodies showed positivity for mast cells, some of which appeared degranulated. Such findings were entirely consistent with an acute systemic anaphylactic reaction triggered by allergy. Therefore, the prisoner’s death was attributed to self-induced food anaphylaxis caused by the ingestion of peaches. This conclusion was achieved based only on circumstantial data, anamnestic information, autopsy findings, and multiple laboratory results. This integrated approach should be used to pursue a post-mortem diagnosis of anaphylaxis.