Alpha-Tryptase as a Risk-Modifying Factor for Mast Cell-Mediated Reactions.

PURPOSE OF REVIEW: To provide an overview on the current understanding of genetic variability in human tryptases and summarize the literature demonstrating the differential impact of mature tryptases on mast cell-mediated reactions and associated clinical phenotypes. RECENT FINDINGS: It is becoming increasingly recognized that tryptase gene composition, and in particular the common genetic trait hereditary alpha-tryptasemia (HαT), impacts clinical allergy. HαT has consistently been associated with clonal mast cell disorders (MCD) and has also been associated with more frequent anaphylaxis among these patients, and patients in whom no allergic trigger can be found, specifically idiopathic anaphylaxis. Additionally, more severe anaphylaxis among Hymenoptera venom allergy patients has been linked to HαT in both retrospective and prospective studies. An increased relative number of α-tryptase-encoding gene copies, even in the absence of HαT, has also been associated with systemic mastocytosis and has been shown to positively correlate with the severity of mast cell-mediated reactions to vibration and food. These findings may be due to increased generation of α/ß-tryptase heterotetramers and differences in their enzymatic activity relative to ß-tryptase homotetramers. HαT is a naturally occurring overexpression model of α-tryptase in humans. Increased relative α-tryptase expression modifies immediate hypersensitivity symptoms and is associated with more frequent and severe mast cell-mediated reactions, ostensibly due to increased α/ß-tryptase heterotetramer production.

Reversible Elevation of Tryptase Over the Individual's Baseline: Why is It the Best Biomarker for Severe Systemic Mast Cell Activation and MCAS?

PURPOSE OF REVIEW: Mast cell (MC) activation syndromes (MCAS) are conditions defined by recurrent episodes of severe systemic anaphylaxis or similar systemic events triggered by MC-derived mediators that can be measured in biological fluids. Since some symptoms of MC activation may occur due to other, non-MC etiologies and lead to confusion over diagnosis, it is of crucial importance to document the involvement of MC and their products in the patients´ symptomatology. RECENT FINDINGS: The most specific and generally accepted marker of severe systemic MC activation is an event-related, transient increase in the serum tryptase level over the individual baseline of the affected individual. However, baseline concentrations of serum tryptase vary among donors, depending on the genetic background, age, kidney function, and underlying disease. As a result, it is of critical importance to provide a flexible equation that defines the diagnostic increase in tryptase qualifying as MCAS criterion in all patients, all situations, and all ranges of baseline serum tryptase. In 2012, the consensus group proposed the 120% + 2 ng/ml formula, which covers the great majority of groups, including cases with low, normal, or elevated basal serum tryptase level. This formula has been validated in subsequent studies and has proven to be a robust and consistent diagnostic criterion of MCAS. The present article is discussing the impact of this formula and possible limitations as well as alternative markers and mediators that may be indicative of MCAS.

Simulation training for medical emergencies: Evaluation of dentists' long-term learning skills and confidence.

INTRODUCTION: As the population ages and more patients experience medical emergencies during dental treatments, dentists must competently and confidently manage these situations. We developed a simulation training course for medical emergencies in the dental setting using an inexpensive vital sign simulation app for smartphones/tablets without the need for an expensive simulator. However, the duration for which this effect is maintained is unclear. This study was performed to evaluate the long-term educational effect at 3, 6, and 12 months after taking the course. MATERIALS AND METHODS: Thirty-nine dental residents participated in this course. Scenarios included vasovagal syncope, anaphylaxis, hyperventilation syndrome, and acute coronary syndrome, each of which the participants had to diagnose and treat. The participants were evaluated using a checklist for anaphylaxis diagnosis and treatment skills immediately after and 3, 6, and 12 months after the course. The participants were also surveyed about their confidence in diagnosing and treating these conditions by questionnaire before, immediately after, and 3, 6, and 12 months after the course. RESULTS: The checklist scores for anaphylaxis were significantly lower at 3, 6, and 12 months after the course than immediately after the course. The percentage of participants who provided a correct diagnosis and appropriate treatment for vasovagal syncope, hyperventilation syndrome, and acute coronary syndrome was lower at all reassessments than immediately after the course. CONCLUSION: Because medical emergency management skills and confidence declined within 3 months, it would be useful to introduce a refresher course approximately 3 months after the initial course to maintain skills and confidence.

Perioperative hypersensitivity in children: A prospective multidisciplinary study.

BACKGROUND: There are few studies of perioperative hypersensitivity reactions in children. The diagnosis of perioperative hypersensitivity reactions may be under estimated because it is difficult to recognize the reactions. Anaphylaxis may go unnoticed because of patient unconsciousness. Urticaria may be missed due to sterile drapes. The aim of this study was to prospectively evaluate perioperative hypersensitivity reactions. METHODS: In this prospective study, patients with suspected perioperative hypersensitivity reactions aged 0-18 years who underwent surgery at the Department of Pediatric Surgery, Cerrahpasa Faculty of Medicine, between 2019 and 2021 were investigated. Suspected reactions in the perioperative period were graded according to the Ring and Messmer scale. Patients with suspected reactions were examined 4-6 weeks after the reaction. If necessary, specific IgE and basophil activation tests were performed. Reactions of grades III-IV were considered anaphylaxis. If one test modality was strongly positive and there was a relevant time point or repeated allergic reactions, or at least two test modalities were positive, hypersensitivity was confirmed. In all patients, serum tryptase levels were analyzed at the time of the reaction, 2 h after the reaction, and 4-6 weeks after the reaction as part of the allergic evaluation. RESULTS: A total of 29 patients (8 female, 21 male) suspected of having an intraoperative reaction during the study were included in the analysis. Perioperative hypersensitivity reactions were noted in 1 patient. The incidence of perioperative hypersensitivity reactions was reported to be 0.03% (n = 1/2861). While anaphylaxis was confirmed in 1 patient, 5 patients were considered possible anaphylaxis cases. CONCLUSION: Perioperative hypersensitivity reactions can be life-threatening and may recur with further administration. Collaboration between pediatric surgeons, anesthesiologists, and allergists can prevent further reactions. All suspected cases should be evaluated by an experienced allergist soon after the initial reaction.

Fatal and Near-Fatal Anaphylaxis: Data From the European Anaphylaxis Registry and National Health Statistics.

BACKGROUND: Anaphylaxis is a serious systemic reaction-data on fatal and near-fatal reactions are limited. OBJECTIVE: To better understand clinical patterns and risks factors of severe anaphylaxis by a deep analysis of data from fatal and near-fatal anaphylaxis. METHODS: Data from the European Anaphylaxis Registry on fatal/near-fatal anaphylactic reactions and national data on anaphylaxis fatalities were investigated. RESULTS: A total of 305 fatal/near-fatal reactions among children and adults including 35 fatalities from the European Anaphylaxis Registry were identified. The most frequent elicitors were drugs, insects, and food. Male patients (66%/60%) were more frequently affected. Male sex, higher age, concomitant mastocytosis, and cardiovascular disease were associated with a more severe outcome. With increasing reaction severity, skin symptoms were less frequently observed (45% of fatal reactions). In parallel, anaphylaxis mortality rates were studied. The data show that anaphylaxis mortality rates increased in Germany from 0.48 (2009) to 0.59 per 1,000,000 population per year (2020). This increase was apparent only in the female population. In this data set, drugs were the most frequent elicitor of anaphylaxis fatalities, and the rate for this increased over time. CONCLUSIONS: We identified not only elicitors but also individual factors to be associated with an increased risk of fatal anaphylaxis. Such patients should be recognized and managed with great caution. The increase in drug-induced fatalities points to the need for a better allergological care of patients suffering from drug hypersensitivity.

Low Prevalence of Idiopathic Mast Cell Activation Syndrome Among 703 Patients With Suspected Mast Cell Disorders.

BACKGROUND: Idiopathic mast cell activation syndrome (iMCAS) is characterized by severe, episodic systemic mast cell (MC) activation and mediator-related symptoms, an event-related increase in serum tryptase levels, and response to MC-targeted therapies in the absence of underlying IgE-mediated allergy or clonal MC disorder. Studies indicating its prevalence using evidence-based diagnostic criteria are lacking. OBJECTIVE: To assess the prevalence and clinical and laboratory features of patients with iMCAS. METHODS: We conducted a retrospective evaluation of data from 703 consecutive patients (aged ≥18 years) referred to our center based on suspicion of having MC disorders. Patients underwent a thorough clinical workup including patient history, allergy tests, KIT D816V mutation analysis, and/or bone marrow investigation. Disease activity was prospectively assessed during follow-up visits. RESULTS: We identified 31 patients with confirmed iMCAS. Furthermore, hereditary α-tryptasemia was detected in three patients with baseline tryptase levels greater than 8 ng/mL. The most common clinical presentation during MCAS episodes was mucocutaneous symptoms in patients with iMCAS, especially urticaria or angioedema. However, these symptoms were less prevalent in patients with clonal MCAS (P = .015). The duration of diagnostic delay was significantly longer in patients with iMCAS compared to those with clonal MCAS (P = .02). CONCLUSIONS: The overall prevalence of iMCAS was 4.4% in the entire cohort, which indicates that iMCAS is an uncommon condition. To accurately diagnose iMCAS, it is crucial to evaluate suspected patients using the three diagnostic MCAS criteria. This involves performing a comprehensive allergy work-up including laboratory tests and ultrasensitive mutation analysis of KIT D816V. Subsequently, recommended diagnostic algorithms should be applied.

Clinical impact of the TPSAB1 genotype in mast cell diseases: A REMA study in a cohort of 959 individuals.

BACKGROUND: A close association between hereditary alpha-tryptasemia (HAT) and mast cell (MC) disorders has been previously reported. However, the relationship between HAT and the diagnostic subtypes and clinical features of MC disorders still remains to be established. OBJECTIVE: To determine the prevalence of HAT in healthy donors (HD) vs patients with different diagnostic subtypes of MC activation syndromes (MCAS) and mastocytosis, and its relationship with the clinical behavior of the disease. METHODS: A total of 959 subjects were studied including 346 healthy donors (HD), 464 mastocytosis, and 149 non-clonal MCAS patients. Molecular studies to assess the TPSAB1 genotype were performed, and data on serum baseline tryptase (sBT) and basal MC-mediator release episodes and triggers of anaphylaxis were collected. RESULTS: HAT was detected in 15/346 (4%) HD versus 43/149 (29%) non-clonal MCAS and 84/464 (18%) mastocytosis cases. Among mastocytosis, HAT was more frequently found in patients with MC-restricted KITD816V (21% vs. 10% among multilineage KITD816V patients; p = .008). Overall, median sBT was higher in cases presenting with HAT (28.9 vs. 24.5 ng/mL; p = .008), while no significant differences in sBT were observed among HAT+ mastocytosis patients depending on the presence of 1 vs. ≥2 extra copies of the α-tryptase gene (44.1 vs. 35.2 ng/mL, p > .05). In turn, anaphylaxis was more frequently observed in HAT+ versus HAT- mastocytosis patients (76% vs. 65%; p = .018), while HAT+ and HAT- patients who did not refer anaphylaxis as the presenting symptom (n = 308) showed a similar prevalence of subsequent anaphylaxis (35% vs. 36%, respectively). CONCLUSION: The frequency of HAT in MC disorders varies according to the diagnostic subtype of the disease. HAT does not imply a higher risk (and severity) of anaphylaxis in mastocytosis patients in whom anaphylaxis is not part of the presenting symptoms of the disease.

Anaphylaxis: A 2023 practice parameter update.

This practice parameter update focuses on 7 areas in which there are new evidence and new recommendations. Diagnostic criteria for anaphylaxis have been revised, and patterns of anaphylaxis are defined. Measurement of serum tryptase is important for diagnosis of anaphylaxis and to identify underlying mast cell disorders. In infants and toddlers, age-specific symptoms may differ from older children and adults, patient age is not correlated with reaction severity, and anaphylaxis is unlikely to be the initial reaction to an allergen on first exposure. Different community settings for anaphylaxis require specific measures for prevention and treatment of anaphylaxis. Optimal prescribing and use of epinephrine autoinjector devices require specific counseling and training of patients and caregivers, including when and how to administer the epinephrine autoinjector and whether and when to call 911. If epinephrine is used promptly, immediate activation of emergency medical services may not be required if the patient experiences a prompt, complete, and durable response. For most medical indications, the risk of stopping or changing beta-blocker or angiotensin-converting enzyme inhibitor medication may exceed the risk of more severe anaphylaxis if the medication is continued, especially in patients with insect sting anaphylaxis. Evaluation for mastocytosis, including a bone marrow biopsy, should be considered for adult patients with severe insect sting anaphylaxis or recurrent idiopathic anaphylaxis. After perioperative anaphylaxis, repeat anesthesia may proceed in the context of shared decision-making and based on the history and results of diagnostic evaluation with skin tests or in vitro tests when available, and supervised challenge when necessary.

Fatal Hymenoptera Venom-Triggered Anaphylaxis in Patients with Unrecognized Clonal Mast Cell Disorder-Is Mastocytosis to Blame?

Hymenoptera venom-triggered anaphylaxis (HVA) affects up to 8.9% of the general population and is the most frequent cause of anaphylaxis in adults, accounting for approximately 20% of all fatal anaphylaxis cases. Quite often, a fatal reaction is a victim's first manifestation of HVA. Mastocytosis represents one of the most important risk factors for severe HVA. We analyzed patients with documented fatal HVA for the presence of underlying clonal mast cell disorder (cMCD). Here, we report three cases of fatal HVA, with undiagnosed underlying cMCD identified by the presence of the peripheral blood and/or bone marrow KIT p.D816V missense variant postmortem. In the first case, anaphylaxis was the initial episode and was fatal. In the other two cases, both patients were treated with specific venom immunotherapy (VIT), nevertheless, one died of HVA after VIT discontinuation, and the other during VIT; both patients had cardiovascular comorbidities and were taking beta-blockers and/or ACE inhibitors. Our results point to the importance of screening all high-risk individuals for underlying cMCD using highly sensitive molecular methods for peripheral blood KIT p.D816V variant detection, including severe HVA and possibly beekeepers, for proper management and the need for lifelong VIT to prevent unnecessary deaths. Patients at the highest risk of fatal HVA, with concomitant cardiovascular and cMCD comorbidities, might not be protected from field stings even during regular VIT. Therefore, two adrenaline autoinjectors and lifelong VIT, and possibly cotreatment with omalizumab, should be considered for high-risk patients to prevent fatal HVA episodes.

Unexpected cause of Kounis syndrome: hypersensitivity reaction to omeprazole.

Kounis syndrome is a rare type of acute coronary syndrome (ACS) that occurs as a result of an allergic or anaphylactic reaction. Kounis syndrome can be induced by various medications including antibiotics, proton pump inhibitors, antihypertensive medications, corticosteroids, and antineoplastic medications. Additionally, cases of Kounis syndrome associated with lansoprazole and pantoprazole have been previously reported in the literature. In this report, we present a case of Kounis syndrome associated with omeprazole use, and discuss the need for a high index of suspicion as it is often underrecognised.

Drug and Venom Allergy in Mastocytosis.

Patients with mastocytosis have an increased risk for mast cell activation events including anaphylaxis when exposed to certain drugs and Hymenoptera venom. Hypotension and cardiovascular collapse without skin or other systemic manifestations can occur after Hymenoptera stings, during the perioperative period, and after exposure to nonsteroidal ntiinflammatory drugs, opioids, and other mast cell activating medications, including vancomycin and quinolones. This chapter reviews the epidemiology, mechanisms, diagnosis, management, and treatment options for Hymenoptera venom and drug-induced reactions in patients with mastocytosis.

Management of Mediator Symptoms, Allergy, and Anaphylaxis in Mastocytosis.

Mastocytosis is characterized by expansion and activation of clonally aberrant mast cells (MCs) in one or more organ systems. Inappropriate MC activation is a key finding in both allergy and mastocytosis; therefore, symptoms in both conditions show some degree of overlap. When mediator release is excessive and involves multiple systems, anaphylaxis may occur. In mastocytosis, the prevalence of atopy is similar to those of the general population, whereas the incidence of anaphylaxis is significantly higher. The purpose of this review is to discuss features of allergy and anaphylaxis as well as the principles of managing MC mediator release symptoms in mastocytosis.

Anaphylaxis following a pleural puncture bringing back a rock water-like liquid.

INTRODUCTION: Anaphylaxis is a life-threatening medical emergency. Its occurrence in the hospital environment should lead to the first evocation of a drug allergy or a latex allergy. However, many other etiologies need to be investigated early. We publish this case report to highlight a rare differential diagnosis of drug allergy, namely hypersensitivity caused by Ecchinoccocus granulosis. CLINICAL CASE: An 18-year-old female patient with no previous pathological history, from a rural environment, consulted for a 4-month history of right basi-thoracic pain without any other associated clinical sign. Her physical examination revealed a right pleuritic syndrome. Chest radiograph showed a right pleural opacity. The patient had a pleural puncture bringing back a rocky water-like fluid. Five minutes later, the patient had an injection of paracetamol to relieve the pain. Thirty minutes later, plaques of urticaria on the extremities and trunk and arterial hypotension occurred. The diagnosis of grade III anaphylaxis was retained. Following vascular filling and administration of antihistamines, the evolution was rapidly favorable. The thoraco-abdominal ultrasound showing the presence of a ruptured liver hydatid cyst in the pleura. A surgical treatment was thus proposed. Despite contact with latex gloves and the administration of paracetamol after surgery, the patient did not present any allergic reaction. Thus the retained cause of the anaphylaxis was ecchinoccocus granulosis. CONCLUSION: Anaphylaxis following a pleural puncture bringing back a rock water-like liquid must suggest the diagnosis of complicated hydatic cyst.

Severe food allergy reactions are associated with α-tryptase.

BACKGROUND: Increased TPSAB1 copy numbers encoding ⍺-tryptase are associated with severe reactions in adults with Hymenoptera venom allergy, systemic mastocytosis, and idiopathic anaphylaxis. OBJECTIVE: The primary objective was to assess the association between ⍺-tryptase and severity of food allergy. METHODS: A total of 119 subjects underwent tryptase genotyping; 82 of them were from an observational food allergy cohort at the National Institute of Allergy and Infectious Disease (NIAID), and 37 were from a cohort of children who reacted to peanut oral food challenge (OFC) at Lurie Children's Hospital of Chicago. The primary predictor was presence or absence of ⍺-tryptase. The primary outcomes for both cohorts were measures of severity of food allergy reaction. Secondary outcomes included OFC symptom scores (Bock/Practical Allergy [PRACTALL] and Severity Grading Score for Acute Reactions [SGSAR]). Correlation between total α-tryptase isoforms and OFC scores was also assessed to account for gene dosage effects. RESULTS: Among the subjects in the NIAID cohort, the presence of ⍺-tryptase was associated with a higher prevalence of food-triggered anaphylaxis than in those with only ß-tryptase (P = .026). Similarly, only 1 of 6 subjects in the OFC cohort with only ß-tryptase (17%) had a severe reaction, whereas 20 of 31 of subjects with α-tryptase (65%) had a severe reaction (P = .066). Subjects with ⍺-tryptase also had higher total SGSAR scores than did the subjects with no ⍺-tryptase (P = .003). In addition, there were also significant positive correlations between ⍺-tryptase isoform copy numbers and both higher total SGSAR and Bock/PRACTALL OFC scores (P = .008 and P = .003, respectively). CONCLUSION: The presence of α-tryptase in subjects is correlated with a higher prevalence of anaphylaxis or severe reaction to food than in subjects without any α-tryptase.

Characteristics and management of hypersensitivity reactions with rabbit anti-thymocyte globulin in pediatric patients.

Background: Anti-thymocyte globulin (ATG) has been successfully used for decades to prevent graft versus host disease before hematopoietic stem cell transplantation (HSCT) as a part of conditioning regimen. However, sometimes hypersensitivity reactions may limit its use. Objective: To evaluate hypersensitivity reactions experienced during rabbit-ATG infusion among children and present successful desensitization protocol. Methods: The medical records of pediatric patients who were given rabbit-ATG treatment at our tertiary center hospital HSCT unit between 2019 and 2022 were reviewed retrospectively. Diagnosis of the patients, age at the time of HSCT, gender, presence of hypersensitivity reaction to rabbit-ATG, and management were evaluated. Characteristics of the reaction and presence of hypersensitivity reaction to other drugs were also noted. If performed, desensitization protocols were evaluated retrospectively. Results: We evaluated 81 patients; 66.6% of them (n = 54) were boys. The mean age of the patients was 8.78 ± 5.48 years. Hypersensitivity to rabbit-ATG was seen in six patients (7.4%). Four of them (4.9%) had anaphylaxis; two (2.4%) had urticaria. Intradermal test performed to every patient before the first dose of ATG infusion was detected a positive result in 1 patient (1.2%) . None of these seven patients had allergic reactions to other drugs before. Successful ATG desensitization was performed in five patients by using a 12-16 step protocol due to patients' reaction severity. Conclusion: This study aimed to evaluate hypersensitivity reactions with rabbit-ATG in children. A successful desensitization protocol with rabbit-ATG is presented. Desensitization must be performed with an experienced team very carefully in the absence of alternative drug.

Mimics of Allergy and Angioedema: Scombroid, Mast Cell Activation Disorders, and Hereditary Alpha Tryptasemia.

Scombroid poisoning, systemic mastocytosis, and hereditary alpha tryptasemia all present with episodes that resemble allergic reactions. Knowledge regarding systemic mastocytosis and hereditary alpha tryptasemia is quickly evolving. Epidemiology, pathophysiology, and strategies to identify and diagnose are discussed. Evidence-based management in the emergency setting and beyond is also explored and summarized. Key differences are described between these events and allergic reactions.

Hypersensitivity Reaction and Rapid Drug Desensitization with Chemotherapeutics: A Tertiary Reference Center Experiences.

INTRODUCTION: Chemotherapy drugs have been in our lives for a long time, and all agents have the potential to develop hypersensitivity. Rapid drug desensitization is an option when hypersensitivity develops. The aim of this study was to examine the characteristics, diagnostic processes, and treatment results of patients with chemotherapeutic agent hypersensitivity who applied to our tertiary reference center. METHODS: Patients who applied to our tertiary allergy outpatient clinic between January 2016 and September 2022 due to chemotherapy-induced drug hypersensitivity were examined. Demographic data of the patients, cancer diagnoses, chemotherapy regimens, skin tests, premedication scheme, desensitization cycle were evaluated. We applied a 16-step desensitization in patients with index reaction anaphylaxis or positive skin tests. If the index reaction was not anaphylaxis or skin tests were negative, we applied a 12-step desensitization. If the prick test with chemotherapeutic drugs was negative especially with taxanes, premedication was administered. We used the montelukast, cetirizine, and methylprednisolone for premedication. RESULTS: Fifty-one patients were evaluated; 35 (68.6%) were female. The most common malignancy was colorectal cancer in 17 (33.3%) patients. The most common agent responsible for hypersensitivity was oxaliplatin in 17 (33.3%) patients, followed by paclitaxel in 13 (25.4%). When the symptoms of immediate reaction to chemotherapeutic drugs were analyzed as described in the EAACI position paper, only skin and mucosal involvement was seen in 24 (46.8%) patients; only respiratory system involvement or back pain was seen in 3 (6.2%) patients; multisystem involvement meeting the criteria for anaphylaxis was seen in 24 (47%) patients. Skin test was positive in 17 (56.6%) of 30 patients who developed a reaction with platin. Prolonged anaphylaxis was developed in 1 patient, and desensitization was not performed again. Fifty of 51 patients were able to receive the target chemotherapy dose by desensitization. In total, a 172-step desensitization was applied to 51 patients. CONCLUSION: If completing the cycle is considered a treatment success, this was achieved in 98% (50/51) patients with rapid drug desensitization. This gives us the opportunity to use first-line chemotherapy agents.

Investigating the optimal diagnostic value of histamine for diagnosing perioperative hypersensitivity: a prospective, observational study.

Although several guidelines recommend measuring blood tryptase and histamine concentrations to diagnose perioperative anaphylaxis (POA), tryptase measurement is more common. The appropriate timing of blood collection and the diagnostic threshold for histamine measurement are still controversial. To address these issues, histamine concentrations in patients with anaphylaxis and those with anaphylaxis-uncertain were compared in our previous study, the Japanese Epidemiologic Study for Perioperative Anaphylaxis (JESPA). However, because we could not rule out the possibility that the anaphylactic-uncertain group included anaphylactic patients, histamine concentrations were measured in patients who underwent general anesthesia with no complications as controls in the present study. Histamine levels were measured at anesthesia induction (baseline), 30 min (first point), and 2 h (second point) after the start of surgery in 30 control patients. Histamine concentrations in controls were lower than in patients with POA in JESPA at the first and second points. At the first point, a threshold of 1.5 ng/ml resulted in sensitivity of 77% and specificity of 100%. A threshold of 1.1 ng/ml at the second point resulted in sensitivity of 67% and specificity of 87%. Measurement of histamine concentrations within two hours after symptom onset might help diagnose POA.