Case Report: An unusual case of cardiac anaphylaxis in the maintenance phase of vespula venom immunotherapy

Background: Cardiac involvement in anaphylaxis remains difficult to assess; however, histamine release during an anaphylactic reaction can induce functional and metabolic alterations in the myocardium. Mast cells, identified within myocardial fibers, perivascular tissue, and arterial structures, play a crucial role in systemic and cardiac anaphylaxis through the release of inflammatory mediators, including histamine, platelet-activating factor, cytokines, chemokines, tryptase, chymase, prostaglandins, and leukotrienes. Hymenoptera venom immunotherapy (VIT) is the most effective strategy for preventing systemic reactions in sensitized individuals. Although VIT is generally well tolerated, severe allergic reactions can occur, particularly during the build-up phase, while they are rare in the maintenance phase.

Case report: We present the case of a 57-year-old male with a history of severe systemic reactions (SSR) to Vespula stings who experienced cardiac anaphylaxis during the maintenance phase of VIT. He started VIT with a conventional up-dosing schedule, which was well-tolerated. However, during the third monthly maintenance dose, he developed an anaphylactic syncopal episode with a right bundle branch block (RBBB) on ECG. He was treated promptly with adrenaline, corticosteroids, and antihistamines, and his ECG normalized within 20 days.

Conclusions: This case underscores the potential cardiac involvement in anaphylaxis during VIT maintenance and highlights the need to systematically evaluate cardiovascular manifestations during anaphylaxis episodes to optimize risk assessment and management.

Introduction

Cardiac involvement in anaphylaxis is difficult to assess, but it has been described that histamine release during an anaphylactic reaction can cause functional and metabolic changes in the heart (1).

Mast cells identified in human heart are involved in systemic and cardiac anaphylaxis through the release of inflammatory mediators such as histamine, platelet activating factor, cytokines, chemokines, tryptase, chymase, prostaglandins and leukotrienes; in the heart they can be found between myocardial fibers, in the perivascular tissue, in the adventitia and arteria intima (2).

Hymenoptera stings can trigger systemic allergic reactions that range from mild symptoms, such as hives, to severe and potentially fatal anaphylaxis in sensitized individuals (3).

The most effective treatment for preventing systemic reactions upon re-sting, including life-threatening episodes, is Hymenoptera venom immunotherapy (VIT) (4).

The schedule for VIT administration requires an induction phase followed by a maintenance phase; during the induction phase the venom is injected subcutaneously at increasing doses until the cumulative dose of 1 ml at the concentration of 100 microgr/ml (mcg/ml) is reached; in the maintenance phase the venom extract is administered at regular intervals to induce and maintain the state of tolerance (5).

VIT is generally a safe treatment; severe allergic reactions have been reported during the build-up phase of treatment while these events are rare during maintenance therapy (6, 7).

We present the case of a 57-year-old male with a history of severe systemic reactions (SSR) to Vespula stings who developed cardiac anaphylaxis during the maintenance phase of VIT.

In the context of our case report, we conducted a systematic review of the available studies to assess the presence of comparable clinical presentations, focusing on cardiac involvement in anaphylaxis.

Case description

A 57-year-old male with a history of SSR to Hymenoptera stings was referred from the Emergency Department to the Allergy and Clinical Immunology Unit of the University Hospital G. Martino in Messina, Italy, following an anaphylactic episode, characterized by systemic urticaria and syncope, triggered by an Hymenoptera sting. He recovered after treatment with 1 gr of intra venous (i.v.) hydrocortisone, intramuscular (i.m.) chlorpheniramine and 500 mcg i.m. adrenaline. The allergy workup through personal medical history revealed a previous episode, 5 years before, of grade IV anaphylaxis according to Mueller's classification (8), after a wasp sting. At that time the patient had been found unconscious in a public space and urgently transported to the Emergency Department under a red code status. The patient had been advised to undergo an allergic screening to evaluate the feasibility for VIT. However, after recovering from anaphylaxis, he declined further allergy investigations as he could not afford the expenses of VIT. Therefore, he had been instead prescribed an adrenaline auto-injector with instructions on its proper use. After having experienced the second anaphylactic event following a wasp sting, the patient was evaluated in our allergy unit. This time he gave his consent to allergy screening; skin testing with airbone allergens such as dust mites, fungi, pollens, animal dander were negative while skin testing with Vespula, Honey Bee, Polistes and Vespa crabro venom extracts (Anallergo, Scarperia and San Piero, Italy) and venom specific IgE measurements (Pharmacia-Cap System, Stockholm, Sweden) confirmed Hymenoptera venom allergy (HVA) due to sensitization to Vespula venom. Routine blood tests were within normal limits, total IgE was 7.43 KU/L (normal range <100 KU/L) and Baseline Serum Tryptase (BST) levels were 6.8 ng/ml therefore within the normal range of 1.0–11.4 ng/ml (ImmunoCAP Tryptase Fluoroenzyme-immunoassay, Thermo Fisher/Phadia AB, Uppsala, Sweden). The REMA score calculation was applied (9, 10) (Table 1) using a cut-off ≥2 as a high-risk score for clonal mast cell disorders (CMD). The REMA score was calculated according to gender (+1 for males), presence of urticaria as skin symptom during the SR (−2 if present), syncope during the SSR (+3 if present) and BST levels (−1 for levels <15 ng/ml). Therefore, the REMA score resulted in +1, indicating no immediate suspicion of CMD. The patient agreed to initiate VIT as, in the meantime, a VIT treatment, Alutard Vespula (ALK-Abellò, Milan, Italy), had been approved by the European and Italian medicines agencies as a pharmaceutical intervention to be carried out in a hospital setting and supplied in Italy to patients with HVA through the Italian National Health System. The patient commenced VIT with Alutard Vespula, a depot Vespula venom extract adsorbed on aluminum hydroxide. A conventional up-dosing schedule was followed (Table 2) allowing to reach the maintenance dose of 100.000 standard quality units (SQ-U) equal to 100 mcg of Vespula venom extract in 15 weeks. VIT up-dosing was well-tolerated and successfully completed. The maintenance phase was continued monthly with subcutaneous injections (s.i) of 100.000 SQ-U equal to 100 mcg of Vespula venom extract. However, 8 min after the third monthly dose injection, the patient experienced an anaphylactic syncopal episode without any other clinical manifestations such as dyspnea, urticaria, tremors, and nausea. Immediate management of the anaphylactic shock included i.m. administration of 500 mcg of adrenaline followed by 1 g of i.v. hydrocortisone, and 10 mg i.m. chlorpheniramine, along with intravenous fluids. Consciousness was promptly restored, and vital signs were monitored. The ECG (Figure 1A), reviewed online by a cardiologist, showed a right bundle brunch block (RBBB); this sign had never been present in previous ECGs. As cardiac enzymes resulted within normal ranges, no cardiovascular treatment was suggested. Serum tryptase was measured straight after anaphylaxis and it resulted slightly above the normal range (15.6 ng/ml). As the patient recovered completely, after 4 h of clinical observation, he was discharged from hospital.

Table 1

Table 1. The table reports the REMA score developed by the Spanish network on mastocytosis (9, 10), a support tool for determining which patients with previous anaphylaxis require additional diagnostic evaluation.

Table 2

Table 2. The table reports the VIT schedule used, starting with a conventional Up-dosing schedule and followed by monthly maintenance doses every 28 days.

Figure 1

Figure 1. (A) The ECG, performed during the anaphylactic reaction after VIT maintenance dose administration, showed a RBBB. (B) The ECG performed 20 days after the anaphylactic reaction was normal showing sinus rhythm.

Other variables that could have caused a systemic reaction rather than VIT were ruled out as the patient had eaten his usual breakfast 4 h before without taking any drugs.

Twenty days after the event, the patient underwent further cardiology evaluation, and the ECG was normal showing spontaneous normalization (Figure 1B). Another tryptase measurement yielded a value of 11.1 ng/ml.

The above-described severe adverse drug reaction (SAD) has been reported to the Italian medicines' agency with the code number 970329.

Discussion

Hymenoptera VIT is a well-established, highly effective intervention for preventing systemic reactions in patients with HVA (4); adverse reactions during VIT administration, particularly in the build-up phase, have been reported in 16%–40% of patients treated with Apis VIT and in 4%–19% of patients treated with Vespula VIT, while severe allergic reactions are rare (11–14). It has been reported that prophylactic administration of Omalizumab could be considered in patients with previous adverse reactions to VIT, but it is still an off label use (6). This case report underscores the complexity of risk stratification before starting VIT, particularly when BST levels are within normal range. Serum tryptase, a marker of mast cell activation, is reported to have a key role when evaluating the risk of anaphylaxis (15). BST has long been regarded as a biomarker for assessing the risk of SSR in subjects with a diagnosis of HVA (16). Elevated BST levels, particularly those above 11.4 ng/ml, are typically associated with a higher risk of severe anaphylaxis (17). Nevertheless, BST levels of 5 ng/ml or 8 ng/ml were present in subjects with SSR after a field sting; in addition, recent studies have shown that tryptase levels traditionally considered as normal may still portend a higher risk of severe reactions in patients with a history of severe HVA, undergoing VIT (18, 19). Our patient's BST levels, though not initially alarming based on traditional thresholds, increased slightly when evaluated during anaphylaxis. This data is supported by previous findings of serum tryptase levels ≥ 8.23 ng/ml identifying anaphylaxis when the blood is drawn less than 6-h from the beginning of anaphylaxis (20). Routine laboratory tests of anaphylaxis are up to now limited to the evaluation of serum total tryptase levels; further research is still needed to be able to evaluate other biomarkers of anaphylaxis such as PAF, chymase, carboxypeptidase A£, dipeptidyl peptidase, basogranulin, and CCL-2; the half-life of these biomarkers is challenging for their routine measurement in real life (21). A multidisciplinary approach should be or is expected to be used to analyze blood samples collected from anaphylaxis patients in the Emergency Department. Previous studies have reported the involvement of cytokines such as IL-6 and IL-10 in such cases (22). Furthermore, biomarkers of anaphylaxis could also be searched in other body fluids such as urine samples (23). A Spanish network on Mastocytosis has developed a score, the so-called REMA score (9, 10), which is an important support tool for determining which patients with previous anaphylaxis require additional diagnostic evaluation (Table 1). The occurrence of a severe anaphylactic episode during the maintenance phase of VIT in our patient, with a high REMA score, underscores the need for a more personalized approach to anaphylaxis risk assessment, particularly in cases where tryptase levels are only slightly elevated (24–26). Patients with a REMA score of less than 2 and a level in the normal range of tryptase may not require immediate investigation. However, those with higher scores (≥2) often need further diagnostic workup, such as bone marrow biopsy and KIT mutation analysis to rule out clonal mast cell disorders (25, 27). In our patient the SR to the maintenance dose of Vespula VIT caused syncope with ECG alterations; the REMA score this time was >2 because of hypotensive anaphylaxis without skin symptoms, a score very suggestive of a MCD. Unfortunately, all these considerations are not sufficient to predict a possible cardiac involvement during anaphylaxis. The heart is a mast-cell rich organ as the presence of such cells has been shown in the endothelium of heart vessels (28). Mastocyte release of histamine in the heart has been reported to strongly influence ventricular function and cardiac rhythm (29) and plays a role in anaphylaxis as human heart mast cells express immunoglobulin E receptors, the so called FcɛRI (27). It has been reported that cardiovascular collapse can be immunologically induced by intracardial histamine release (30). In experimental anaphylaxis with guinea pig hearts, quick and prolonged decrease of coronary blood flow, abrupt increase of heart rate, transient increase in ventricular contractility, arrhythmias such as idioventricular rhythm and conduction defects, were elicited; the latter ranged from partial to complete atrioventricular block (31). Heart involvement in animal models of systemic anaphylaxis has been reported. Guinea pigs were passively sensitized by anti-ovalbumin rabbit serum and 24 h later their hearts were excised and isolated and anaphylactic challenge was induced by a bolus injection of ovalbumin showing possible involvement of platelet activating factor (PAF) in anaphylaxis (32) while mice were sensitized to hazelnut and after repeated oral allergen challenge expansion of cardiac mastcells in the pericardium and myocardium was shown and IL-6 and CCR1/3 and CXCR2 signaling chemokines were significantly elevated (33). No investigation was carried out to verify if the anaphylactic shock after administration of a maintenance dose of Vespula VIT was caused by an IgE mediated mechanism or by other types of adaptive immune responses mediated via IgG or complement as these investigations are not routinely available; in mice IgG subclasses except IgG3 have shown to be capable of inducing anaphylaxis (34). IgG4, instead, are known to be produced during VIT acting as suppressors of anaphylactic responses inhibiting the activation of effector cells (35). Considering other pathways than IgE-dependent in anaphylaxis is an unmet need for a precision medicine approach of the follow-up of patients with anaphylactic reactions, therefore improving risk stratification (36). Anecdotal case reports have been presented describing electrocardiographic alterations during anaphylactic shock such as widespread ST segment elevation, highlighting that the electrocardiogram (ECG) is an essential procedure during an anaphylactic reaction (37, 38). In this report, the RBBB, which developed during anaphylactic shock from VIT, resolved after anaphylaxis treatment, suggesting a direct hemodynamic or inflammatory mechanism in this otherwise healthy patient. To our knowledge, this is the first reported case of cardiac anaphylaxis secondary to VIT administration Likely, this event occurred as a manifestation of Kounis syndrome (KS) which is a consequence of the release of inflammatory cytokines through mast cell activation in the heart, causing cardiac anaphylaxis with coronary artery vasospasms (2), induced by various conditions, drugs, environmental exposures, foods and coronary stents (39).“Type I” KS occurs in patients with normal coronary arteries, in which an allergic reaction triggers mast cell-mediated vasospasm, inducing transient ischemic ECG changes despite normal cardiac enzymes (40). It is thought that this variant could be a manifestation of endothelial dysfunction secondary to endogen oxidative stress induced mastocytes' degranulation (41). Several pharmacologic and environmental triggers have been identified as a cause of KS (42) including food even in the form of exercise-induced-food-dependent KS (43). Clinical cases of KS have been reported after a Hymenoptera sting, both wasp and bee stings, even in children (44–46). Heart involvement in systemic anaphylaxis caused by other types of immunotherapies, non-VIT, has not yet been reported. To explore whether cases of anaphylaxis with cardiac involvement, particularly a RBBB, during the maintenance phase of VIT, had been previously reported a systematic search on PubMed was conducted. Our initial search on PubMed Advanced Search Builder, using the keywords (cardiac anaphylaxis) AND (VIT)) AND (right bundle branch block), made zero results. We then broadened the search to (cardiac anaphylaxis) AND (VIT), which returned eight results but following a detailed analysis, no articles were found to be relevant. We expanded our search to investigate cardiac involvement in anaphylaxis triggered by drugs, foods, and Hymenoptera stings. The initial search recovered 463 articles on cardiac anaphylaxis associated with drug allergy, 259 articles related to food allergy, and 36 articles concerning Hymenoptera venom allergy. However, many of these studies were not directly relevant to our investigation. To improve specificity, we refined the search by applying filters to include only case reports published in English within the last six years, from January 1, 2019, to January 31, 2025. This approach restricted the results to 25 articles on cardiac anaphylaxis correlated to drug allergy, 7 related to food allergy, and 2 associated with Hymenoptera venom allergy. Each article was then meticulously analyzed, and only those presenting well-documented and clinically significant cardiac involvement were included. Case reports in which there was a pre-existing cardiac condition, or the topic was irrelevant or unrelated to our research were excluded. Following this analysis, 4 studies on cardiac anaphylaxis due to drug allergy and 2 studies related to Hymenoptera stings were included, while no articles on food allergy met the inclusion criteria. The selected studies are summarized in Table 3. The results confirmed the exceptional nature of our cardiac anaphylaxis case report from maintenance VIT, as no documented case matched our exact criteria. This finding highlights the need for further research to deepen our understanding of this uncommon presentation and its underlying mechanisms.

Table 3

Table 3. The table reports the articles selected through PubMed research.

Conclusions

The clinical case described in this article emphasizes that even during the maintenance phase, generally associated with reduced risk of reactions to VIT, severe reactions can occur.

Even patients with a previous low REMA score but moderately elevated tryptase levels should be carefully monitored, as they may still harbor a latent risk for severe anaphylaxis. A more nuanced and personalized approach to risk stratification, considering all relevant clinical and biochemical markers, is essential to optimize patient safety and prevent life-threatening reactions during long-term VIT treatment.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving humans were approved by Ethics committee of the G.Martino Hospital of Messina, Italy. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author contributions

SB: Conceptualization, Formal analysis, Investigation, Writing – original draft. FB: Formal analysis, Investigation, Writing – original draft. SG: Writing – review & editing. LR: Conceptualization, Formal analysis, Investigation, Supervision, Writing – original draft, Writing – review & editing.

Funding

The author(s) declare that no financial support was received for the research and/or publication of this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

Publisher's note

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References

1. Bani D, Nistri S, Mannaioni PF, Masini E. Cardiac anaphylaxis: pathophysiology and therapeutic perspectives. Curr Allergy Asthma Rep. (2006) 6(1):14–9. doi: 10.1007/s11882-006-0004-9

PubMed Abstract | Crossref Full Text | Google Scholar

2. Kounis NG, Mazarakis A, Tsigkas G, Giannopoulos S, Goudevenos J. Kounis syndrome: a new twist on an old disease. Future Cardiol. (2011) 7(6):805–24. doi: 10.2217/fca.11.63

PubMed Abstract | Crossref Full Text | Google Scholar

3. Bilò MB. Anaphylaxis caused by hymenoptera stings: from epidemiology to treatment. Allergy. (2011) 66(s95):35–7. doi: 10.1111/j.1398-9995.2011.02630.x

PubMed Abstract | Crossref Full Text | Google Scholar

4. Kayikci H, Can Bostan O, Tuncay G, Cihanbeylerden M, Damadoglu E, Karakaya G, et al. Efficacy and safety of hymenoptera venom immunotherapy. Allergy Asthma Proc. (2024) 45(4):268–75. doi: 10.2500/aap.2024.45.240035

PubMed Abstract | Crossref Full Text | Google Scholar

5. Bilò MB, Pravettoni V, Bignardi D, Bonadonna P, Mauro M, Novembre E, et al. Hymenoptera venom allergy: management of children and adults in clinical practice. J Investig Allergol Clini Immunol. (2019) 29(3):180–205. doi: 10.18176/jiaci.0310

PubMed Abstract | Crossref Full Text | Google Scholar

6. Ruëff F, Bauer A, Becker S, Brehler R, Brockow K, Chaker AM, et al. Diagnosis and treatment of hymenoptera venom allergy. Allergologie Select. (2023) 7(1):154–90. doi: 10.5414/ALX02430E

PubMed Abstract | Crossref Full Text | Google Scholar

7. Floyd ML, Adams KE, Golden DBK. Updates and recent advances on venom immunotherapy. Curr Treat Options Allergy. (2023) 10(2):196–214. doi: 10.1007/s40521-023-00336-7

PubMed Abstract | Crossref Full Text | Google Scholar

8. Mueller HL. Diagnosis and treatment of insect sensitivity. J Asthma Res. (1966) 3(4):331–33. doi: 10.3109/02770906609106941

PubMed Abstract | Crossref Full Text | Google Scholar

9. Alvarez-Twose I, González-de-Olano D, Sánchez-Muñoz L, Matito A, Jara-Acevedo M, Teodosio C, et al. Validation of the REMA score for predicting mast cell clonality and systemic mastocytosis in patients with systemic mast cell activation symptoms. Int Arch Allergy Appl Immunol. (2012) 157(3):275–80. doi: 10.1159/000329856

PubMed Abstract | Crossref Full Text | Google Scholar

10. Sánchez-Muñoz L, Morgado JM, Álvarez-Twose I, Matito A, Garcia-Montero AC, Teodosio C, et al. Diagnosis and classification of mastocytosis in non-specialized versus reference centres: a Spanish network on mastocytosis (REMA) study on 122 patients. Br J Haematol. (2016) 172(1):56–63. doi: 10.1111/bjh.13789

PubMed Abstract | Crossref Full Text | Google Scholar

11. Brunetto S, Gammeri L, Buta F, Gangemi S, Ricciardi L. Hymenoptera venom immunotherapy: safety and efficacy of an accelerated induction regimen with depot aluminum adsorbed extracts. Allergy Asthma Proc. (2024) 45(3):195–200. doi: 10.2500/aap.2024.45.240011

PubMed Abstract | Crossref Full Text | Google Scholar

12. Ruëff F, Przybilla B, Biló MB, Müller U, Scheipl F, Aberer W, 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(1):105–111.e5. doi: 10.1016/j.jaci.2010.04.025

PubMed Abstract | Crossref Full Text | Google Scholar

13. Mosbech H, Müller U, On Behalf Of The Study Group*. Side-effects of insect venom immunotherapy:results from an EAACI multicenter study. Allergy. (2000) 55(11):1005–10. doi: 10.1034/j.1398-9995.2000.00587.x

PubMed Abstract | Crossref Full Text | Google Scholar

14. Korošec P, Žiberna K, Šilar M, Dežman M, Smodiš NČ, Rijavec M, et al. Immunological and clinical factors associated with adverse systemic reactions during the build-up phase of honeybee venom immunotherapy. Clin Exper Aller. (2015) 45(10):1579–89. doi: 10.1111/cea.12582

PubMed Abstract | Crossref Full Text | Google Scholar

15. Kopač P, Custovic A, Zidarn M, Šilar M, Šelb J, Bajrović N, et al. Biomarkers of the severity of honeybee sting reactions and the severity and threshold of systemic adverse events during immunotherapy. J Aller Clin Immunol Pract. (2021) 9(8):3157–3163.e5. doi: 10.1016/j.jaip.2021.04.045

PubMed Abstract | Crossref Full Text | Google Scholar

16. Ruëff F, Przybilla B, Biló MB, Müller U, Scheipl F, Aberer W, et al. Predictors of severe systemic 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(5):1047–54. doi: 10.1016/j.jaci.2009.08.027

PubMed Abstract | Crossref Full Text | Google Scholar

17. Guenova E, Volz T, Eichner M, Hoetzenecker W, Caroli U, Griesinger G, et al. Basal serum tryptase as risk assessment for severe hymenoptera sting reactions in elderly. Allergy. (2010) 65(7):919–23. doi: 10.1111/j.1398-9995.2009.02302.x

PubMed Abstract | Crossref Full Text | Google Scholar

18. Francuzik W, Ruëff F, Bauer A, Bilò MB, Cardona V, Christoff G, et al. Phenotype and risk factors of venom-induced anaphylaxis: a case-control study of the European anaphylaxis registry. J Allergy Clin Immunol. (2021) 147(2):653–662.e9. doi: 10.1016/j.jaci.2020.06.008

PubMed Abstract | Crossref Full Text | Google Scholar

19. Bonadonna P, Korosec P, Nalin F, Golden DBK. Venom anaphylaxis: decision points for a more aggressive workup. J Aller Clin Immunol Pract. (2023) 11(7):2024–31. doi: 10.1016/j.jaip.2023.04.016

PubMed Abstract | Crossref Full Text | Google Scholar

20. Enrique E, García-Ortega P, Gaig P, Richart C, Sotorra O. Usefulness of UniCAP-tryptase fluoroimmunoassay in the diagnosis of anaphylaxis. Allergy. (1999) 54(6):602–6. doi: 10.1034/j.1398-9995.1999.00882.x

PubMed Abstract | Crossref Full Text | Google Scholar

21. Beck SC, Wilding T, Buka RJ, Baretto RL, Huissoon AP, Krishna MT. Biomarkers in human anaphylaxis: a critical appraisal of current evidence and perspectives. Front Immunol. (2019) 10:494. doi: 10.3389/fimmu.2019.00494

PubMed Abstract | Crossref Full Text | Google Scholar

22. Dass C, Eyck PT, Ballas Z, Lee S. Characterization of Serum biomarkers during anaphylaxis in emergency department patients. J Aller Clin Immunol Pract. (2020) 8(9):3213–3215.e1. doi: 10.1016/j.jaip.2020.05.010

PubMed Abstract | Crossref Full Text | Google Scholar

23. Pampura A, Esakova N, Zimin S, Filippova E. Anaphylaxis biomarkers: present and future. Eur Ann Allergy Clin Immunol. (2024) 56(06):243. doi: 10.23822/EurAnnACI.1764-1489.350

PubMed Abstract | Crossref Full Text | Google Scholar

24. Schwartz L. Tryptase, a mediator of human mast cells. J Allergy Clin Immunol. (1990) 86(4):594–98. doi: 10.1016/S0091-6749(05)80222-2

PubMed Abstract | Crossref Full Text | Google Scholar

25. Escribano L, Garcia Montero AC, Núñez R, Orfao A. Flow cytometric analysis of normal and neoplastic mast cells: role in diagnosis and follow-up of mast cell disease. Immunol Allergy Clin North Am. (2006) 26(3):535–47. doi: 10.1016/j.iac.2006.05.008

PubMed Abstract | Crossref Full Text | Google Scholar

26. Valent P, Akin C, Escribano L, Födinger M, Hartmann K, Brockow K, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Investig. (2007) 37(6):435–53. doi: 10.1111/j.1365-2362.2007.01807.x

PubMed Abstract | Crossref Full Text | Google Scholar

27. Valent P, Akin C, Metcalfe DD. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood. (2017) 129(11):1420–27. doi: 10.1182/blood-2016-09-731893

PubMed Abstract | Crossref Full Text | Google Scholar

28. Genovese A, Spadaro G. Highlights in cardiovascular effects of histamine and H _I -receptor ansgonists. Allergy. (1997) 52(s34):67–78. doi: 10.1111/j.1398-9995.1997.tb04813.x

PubMed Abstract | Crossref Full Text | Google Scholar

29. Triggiani M, Patella V, Staiano RI, Granata F, Marone G. Allergy and the cardiovascular system. Clin Exp Immunol. (2008) 153(Supplement_1):7–11. doi: 10.1111/j.1365-2249.2008.03714.x

PubMed Abstract | Crossref Full Text | Google Scholar

30. Felix SB, Baumann G, Berdel WE. Systemic anaphylaxis—separation of cardiac reactions from respiratory and peripheral vascular events. Research in Experimental Medicine. (1990) 190(1):239–52. doi: 10.1007/BF00000029

PubMed Abstract | Crossref Full Text | Google Scholar

31. Kounis NG, Cervellin G, Koniari I, Bonfanti L, Dousdampanis P, Charokopos N, et al. Anaphylactic cardiovascular collapse and Kounis syndrome: systemic vasodilation or coronary vasoconstriction? Ann Transl Med. (2018) 6(17):332–332. doi: 10.21037/atm.2018.09.05

PubMed Abstract | Crossref Full Text | Google Scholar

32. Tosaki A, Koltai M, Braquet P, Szekeres L. Possible involvement of platelet activating factor in anaphylaxis of passively sensitised, isolated Guinea pig hearts. Cardiovasc Res. (1989) 23(8):715–22. doi: 10.1093/cvr/23.8.715

PubMed Abstract | Crossref Full Text | Google Scholar

33. Gonipeta B, Para R, He Y, Srkalovic I, Ortiz T, Kim E, et al. Cardiac MMCP-4+ mast cell expansion and elevation of IL-6, and CCR1/3 and CXCR2 signaling chemokines in an adjuvant-free mouse model of tree nut allergy. Immunobiology. (2015) 220(5):663–72. doi: 10.1016/j.imbio.2014.11.012

PubMed Abstract | Crossref Full Text | Google Scholar

34. Vitte J, Vibhushan S, Bratti M, Montero-Hernandez JE, Blank U. Allergy, anaphylaxis, and nonallergic hypersensitivity: igE, mast cells, and beyond. Med Princ Pract. (2022) 31(6):501–15. doi: 10.1159/000527481

PubMed Abstract | Crossref Full Text | Google Scholar

35. Blank S, Grosch J, Ollert M, Bilò MB. Precision medicine in hymenoptera venom allergy: diagnostics, biomarkers, and therapy of different endotypes and phenotypes. Front Immunol. (2020) 11:579409. doi: 10.3389/fimmu.2020.579409

PubMed Abstract | Crossref Full Text | Google Scholar

36. Galvan-Blasco P, Gil-Serrano J, Sala-Cunill A. New biomarkers in anaphylaxis (beyond tryptase). Curr Treat Options Allergy. (2022) 9(4):303–22. doi: 10.1007/s40521-022-00326-1

PubMed Abstract | Crossref Full Text | Google Scholar

37. Mirijello A, Maddalena D’Errico M, Piscitelli P, Cosmo SD. Electrocardiographic alterations and raised procalcitonin levels during anaphylactic shock. BMJ Case Rep. (2020) 13(1):e233521. doi: 10.1136/bcr-2019-233521

PubMed Abstract | Crossref Full Text | Google Scholar

38. Ralapanawa DMP, Kularatne SAM. Kounis syndrome secondary to amoxicillin/clavulanic acid administration: a case report and review of literature. BMC Res Notes. (2015) 8(1):97. doi: 10.1186/s13104-015-1072-5

PubMed Abstract | Crossref Full Text | Google Scholar

39. Kounis NG. Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med (CCLM). (2016) 54(10):1545–59. doi: 10.1515/cclm-2016-0010

PubMed Abstract | Crossref Full Text | Google Scholar

40. Abdelghany M, Subedi R, Shah S, Kozman H. Kounis syndrome: a review article on epidemiology, diagnostic findings, management and complications of allergic acute coronary syndrome. Int J Cardiol. (2017) 232:1–4. doi: 10.1016/j.ijcard.2017.01.124

PubMed Abstract | Crossref Full Text | Google Scholar

41. Ricciardi L, Furci F, Casciaro M, Salvo ED, Cristani M, Tigano V, et al. Drug induced kounis syndrome: does oxidative stress play a role? Clin Mol Allergy. (2018) 16(1):21. doi: 10.1186/s12948-018-0099-2

PubMed Abstract | Crossref Full Text | Google Scholar

42. Alblaihed L, Huis in ‘t Veld MA. Allergic acute coronary syndrome—kounis syndrome. Emerg Med Clin North Am. (2022) 40(1):69–78. doi: 10.1016/j.emc.2021.08.010

PubMed Abstract | Crossref Full Text | Google Scholar

43. Kounis NG, Koniari I, Tsigkas G, Soufras GD, Chourdakis E, Davlouros P, et al. Exercise-Induce anaphylaxis, food-dependent exercise-induce anaphylaxis, cholinergic Urticaria and kounis syndrome. Neth J Med. (2019) 77(1):38–9.30774109

PubMed Abstract | Google Scholar

44. Selcuk A, Gullu UU. Kounis syndrome after a wasp sting. J Paediatr Child Health. (2022) 58(1):173–74. doi: 10.1111/jpc.15423

PubMed Abstract | Crossref Full Text | Google Scholar

45. Lin W-J, Zhang Y-q, Fei Z, Liu D-d, Zhou X-H. Kounis syndrome caused by bee sting: a case report and literature review. Cardiovasc J Afr. (2023) 34(4):64–7. doi: 10.5830/CVJA-2022-042

PubMed Abstract | Crossref Full Text | Google Scholar

46. Bodur İ, Yaradılmış RM, Güngör A, Sel K, Tuygun N. A rare pediatric case of kounis syndrome after bee sting. Acta Clin Belg. (2022) 77(4):782–84. doi: 10.1080/17843286.2021.1981587

PubMed Abstract | Crossref Full Text | Google Scholar

47. Ebrahimi P, Nazari R, Senobari N, Mousavinezhad SM, Ghadimi DJ, Soleimani H. Kounis syndrome type I induced by an intramuscular injection of diclofenac: a literature review based on a case report. Clin Case Rep. (2024) 12(7):e9198. doi: 10.1002/ccr3.9198

PubMed Abstract | Crossref Full Text | Google Scholar

48. Morin S, Boroli F, Vandenberghe-Durr S, Allali D, Masouridi-Levrat S, Chalandon Y, et al. Severe anaphylaxis after chimeric antigen receptor T-cell injection: a case report. EJHaem. (2024) 5(3):603–6. doi: 10.1002/jha2.874

PubMed Abstract | Crossref Full Text | Google Scholar

49. Gan K, Ma D. Hypersensitivity reaction to nedaplatin: a case report and literature review. Medicine (Baltimore). (2023) 102(50):e36690. doi: 10.1097/MD.0000000000036690

PubMed Abstract | Crossref Full Text | Google Scholar

50. Erdogan E, Cap M, Kus G, Gokhan C, Kilic Y. An unusual case of concurrent Kounis syndrome and prolonged QT in a young patient. Cardiol Young. (2022) 32(5):824–26. doi: 10.1017/S1047951121003838

PubMed Abstract | Crossref Full Text | Google Scholar

51. Kawaguchi S, Kuroshima T, Namba R, Satou H, Kashiwagi R, Abe A, et al. A case of repeated Kounis syndrome after anaphylactic shock: a note for disease management. Acute Medicine & Surgery. (2024) 11(1):e908. doi: 10.1002/ams2.908

PubMed Abstract | Crossref Full Text | Google Scholar

52. Mondello C, Baldino G, Cianci V, Forzese E, Asmundo A, Ieni A, et al. Postmortem biochemistry and immunohistochemistry in anaphylactic death due to hymenoptera sting: a forensic case report. Int J Environ Res Public Health. (2023) 20(9):5640. doi: 10.3390/ijerph20095640

PubMed Abstract | Crossref Full Text | Google Scholar