We present a case of a 52-year-old patient suffering from multi-phasic life-threatening anaphylaxis refractory to epinephrine treatment. Extracorporeal membrane oxygenation (ECMO) therapy was initiated as the ultima ratio to stabilize the patient hemodynamically during episodic severe bronchospasm. ECMO treatment was successfully weaned after 4 days. Mastocytosis was diagnosed as the underlying condition. Although epinephrine is recommended as a first-line treatment for anaphylaxis, this impressive case provides clear evidence of its limited therapeutic success and emphasizes the need for causal therapies

Alexandra-Maria Warenits

Bernd Jilma

Christian Schoergenhofer

Elisabeth Lobmeyr

Florian Ettl

Georg Gelbenegger

Juergen Grafeneder

Michael Schwameis

Nina Buchtele

Thomas Staudinger

Wolfgang R. Sperr

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TYPE Community Case StudyPUBLISHED 29 July 2022DOI 10.3389/falgy.2022.934436OPEN ACCESSEDITED BYSiddanakoppalu N. Pramod,Davangere University, IndiaREVIEWED BYMatthew P. Giannetti,Brigham and Women’s Hospital andHarvard Medical School, United StatesWarwick Wolf Butt,Royal Children’s Hospital, Australia*CORRESPONDENCEBernd JilmaBernd.Jilma@meduniwien.ac.atSPECIALTY SECTIONThis article was submitted toDrug, Venom & Anaphylaxis,a section of the journalFrontiers in AllergyRECEIVED 02 May 2022ACCEPTED 01 July 2022PUBLISHED 29 July 2022CITATIONGrafeneder J, Ettl F, Warenits A-M,Buchtele N, Lobmeyr E, Staudinger T,Schwameis M, Sperr WR,Gelbenegger G, Schoergenhofer Cand Jilma B (2022) Multi-phasiclife-threatening anaphylaxis refractoryto epinephrine managed byextracorporeal membraneoxygenation (ECMO): A case report.Front. Allergy 3:934436.doi: 10.3389/falgy.2022.934436COPYRIGHT© 2022 Grafeneder, Ettl, Warenits,Buchtele, Lobmeyr, Staudinger,Schwameis, Sperr, Gelbenegger,Schoergenhofer and Jilma. This is anopen-access article distributed underthe terms of the Creative CommonsAttribution License (CC BY). The use,distribution or reproduction in otherforums is permitted, provided theoriginal author(s) and the copyrightowner(s) are credited and that theoriginal publication in this journal iscited, in accordance with acceptedacademic practice. No use, distributionor reproduction is permitted whichdoes not comply with these terms.Multi-phasic life-threateninganaphylaxis refractory toepinephrine managed byextracorporeal membraneoxygenation (ECMO): A casereportJuergen Grafeneder1, Florian Ettl1,Alexandra-Maria Warenits1, Nina Buchtele2,Elisabeth Lobmeyr2, Thomas Staudinger2,Michael Schwameis1, Wolfgang R. Sperr2,Georg Gelbenegger3, Christian Schoergenhofer3 andBernd Jilma3*1Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria, 2Intensive CareUnit 13i2, Division of Hematology and Hemostaseology, Department of Internal Medicine I, MedicalUniversity of Vienna, Vienna, Austria, 3Department of Clinical Pharmacology, Medical University ofVienna, Vienna, AustriaWe present a case of a 52-year-old patient su ering from multi-phasiclife-threatening anaphylaxis refractory to epinephrine treatment.Extracorporeal membrane oxygenation (ECMO) therapy was initiated asthe ultima ratio to stabilize the patient hemodynamically during episodicsevere bronchospasm. ECMO treatment was successfully weaned after 4days. Mastocytosis was diagnosed as the underlying condition. Althoughepinephrine is recommended as a first-line treatment for anaphylaxis, thisimpressive case provides clear evidence of its limited therapeutic success andemphasizes the need for causal therapies.KEYWORDSmastocytosis, MCAS, anaphylactic shock, bronchospasm, respiratory failure,epinephrine resistance, extracorporeal membrane oxygenation (ECMO)IntroductionMastocytosis is an orphan disease characterized by an increase of neoplastic mastcells (1). Most patients present with non-advanced mastocytosis and have a normal ornear-normal life expectancy. The KIT D816V gene activating mutation is consideredcentral to the pathogenesis and is present in the vast majority (>80%) of systemicmastocytosis (2). This gene regulates the proliferation and differentiation of mastcells. Mediator-related symptoms may include anaphylaxis, bone pain, gastrointestinalFrontiers in Allergy 01 frontiersin.orgGrafeneder et al. 10.3389/falgy.2022.934436problems, fatigue, and osteoporosis. Mast cell activation leadsto degranulation of mast cells (3) and subsequent tryptase andhistamine release.ContextInitial presentationPre-Hospital: A 52-year-old patient without known allergiesdeveloped sudden respiratory distress and made an emergencycall (12:35 pm). When the paramedics arrived, she was hypoxicand hypotensive (oxygen saturation (SpO2): 87%, respiratoryrate: 20/min, blood pressure: 90/50 mmHg, heart rate:120/min). Oxygen insufflation (10 L/min) was initiated, and shereceived intravenous phenylephrine, inhaled salbutamol, andipratropium bromide. The patient’s medical history includedarterial hypertension (treated with carvedilol 25mg in theevening), recurring panic attacks (treated with alprazolam0.5mg at night), and a subtotal thyroidectomy 30 years ago(100 µg levothyroxine in the morning for substitution). Therewas no recent change in medication or history of hemodynamicinstability. There were no known triggers for this event.Clinical courseDay 1: On arrival at the emergency department (at1:23 pm) the patient was hemodynamically unstable andoxygen saturation was deteriorating (SpO2 83%) despite oxygeninsufflation (15 L/min). Increasing doses of norepinephrineand maximum non-invasive oxygen support failed to stabilizethe patient. Following endotracheal intubation and initiationof continuous epinephrine infusion (maximum dose: 0.48µg/kg/min) instead of norepinephrine, the patient could bestabilized. Contrast-enhanced computed tomography ruledout pulmonary embolism and aortic dissection. Immediatelyfollowing the scan, the patient developed flush/urticaria, redconjunctivas, and respiratory instability, needing increasedrespiratory support. Prednisolone 250mg and the histamineH1 receptor blocker diphenhydramine 60mg were administeredfor a suspected anaphylactic reaction. Subsequently, the patientstabilized, and the dose of continuous epinephrine infusioncould be substantially reduced (0.01 µg/kg/min). The patientwas normotensive (131/79 mmHg) albeit tachycardic (131min−1), and acidotic (pH: 7.23) despite mechanical ventilation(FiO2: 0.7, PEEP: 6 mbar, pressure support: 13 mbar, respiratoryrate: 18 min−1 under analgo-sedation using propofol andfentanyl) at 6:00 pm. Then, 30min later, she developedanother bout of anaphylaxis (Figure 1) and rapidly deterioratedwith a fall in blood pressure (>30%) to 70/47 mmHg.Despite an increase in the continuous epinephrine infusionto 0.357 µg/kg/min, the mean arterial blood pressure didnot increase to >60 mmHg during the next hour. Onlywith the addition of norepinephrine (0.238 µg/kg/min), theblood pressure stabilized at >70 mmHg at around 8:15pm. However, severe bronchospasm rapidly aggravated therespiratory compromise. Treatment with inhaled fenoterol,ipratropium bromide, and epinephrine as well as intravenouslyand subcutaneously administered terbutaline sulfate resulted ina brief period of stabilization. Around 9:00 pm another bout ofanaphylaxis occurred with flushing, severe bronchospasm, andhemodynamic instability. Stabilization was not achieved despitecontinuous epinephrine (0.5 µg/kg/min) support, intensifiedanalgo-sedation (addition of ketamine), and muscle relaxation.The systolic blood pressure dropped to 68 mmHg, whilethe SpO2 stayed above 93%. A venous-arterial (femoral-femoral) extracorporeal membrane oxygenation (ECMO) hadto be initiated as an ultima ratio for sufficient hemodynamicsupport (blood flow 2.7 l/min, FiO2 1). Thereafter thepatient received another dose of 250mg methylprednisolone(10:00 pm) and 120mg diphenhydramine (10:00 pm and2:00 am). Ketamine was terminated due to lack of effect,and sedation was switched to midazolam alone to test forsoy allergy.Day 2: The patient suffered several further severe boutsof anaphylaxis, during which the hemodynamic situationwas barely manageable despite ECMO (blood flow 3 l/minflow, FiO2 1.0), and ventilation was virtually impossible.Catecholamine and respiratory support were increasedsubstantially during these episodes, and inhalative epinephrineand additional fluid substitution were given. After roughly 24hours, sedation was switched back to propofol. Severe mastcell activation was suspected because tryptase levels wereincreased >50-fold the upper normal limit, and omalizumab300mg was injected subcutaneously (Figure 2). Later thisday the patient suffered another episode of bronchospasm,which resolved after epinephrine inhalation, and systolic bloodpressure stabilized at >90 mmHg about 60 h after the onsetof anaphylaxis.Day 3: The patient remained stable, catecholamines weretapered (reduced), and respiratory support was decreased.Day 4–9: The ECMO was successfully explanted onday 4 when tachycardia disappeared. The patient wassuccessfully extubated on day 5. The molecular workupof the peripheral blood and the bone marrow revealedthe KIT D816V mutation. The bone marrow biopsy (notthe smear) showed 40% infiltration with spindle mastcells with the abnormal expression of CD2 and CD25,diagnosing indolent systemic mastocytosis. Prophylactictreatment with antihistamines was instigated. Thepatient was transferred to a normal ward as no furtherevents occurred.Normal ward: The patient remained stable for another13 days on the normal ward and was discharged ingood health.Frontiers in Allergy 02 frontiersin.orgGrafeneder et al. 10.3389/falgy.2022.934436FIGURE 1Heart rate (HR) and mean arterial pressure (MAP) within the first 36h after admission to the intensive care unit. ECMO, extracorporeal membraneoxygenation.FIGURE 2Time course of tryptase levels within the first days and follow-up. The half-life of tryptase between days 2 and 5 was about 32h. This is in starkcontrast to the normal tryptase half-life of 2 h. This indicates ongoing mast cell activation for a couple of days after the initial peak. ECMO,extracorporeal membrane oxygenation.DiscussionThis patient with mastocytosis developedmultiphasic severe anaphylactic shocks; includingthe pre-hospital phase, 6 episodes of anaphylaxisoccurred within 30 h with a remarkable rhythm(Figure 1).The ECMO support was vital due to repeated life-threatening hypoxia caused by bronchospasms and severecirculatory instability. Although histamine plays a key roleFrontiers in Allergy 03 frontiersin.orgGrafeneder et al. 10.3389/falgy.2022.934436in bronchospasm, antihistamines remain controversial inanaphylaxis. The likely reason for their ineffectiveness isthat they are easily overwhelmed by excessive histamineconcentrations (4) >5-fold the upper normal limit (<1 ng/mL)(5), whereas in severe anaphylaxis histamine concentrationsof >100 ng/mL have been reported (6). A Cochranesystematic review found no evidence of antihistamineefficacy in anaphylaxis (7). In this case the patient’s conditionworsened despite the repeated infusion of antihistaminesand glucocorticoids.Epinephrine is recommended as a first-line treatment foranaphylaxis (8), although there is no supporting evidence fromrandomized controlled trials. To our knowledge, there is nostudy investigating the role of epinephrine in the treatment ofmast cell activation syndrome. It appears that up-titration ofepinephrine to 0.357 µg/kg/min over 50min neither stabilizedthe mean arterial pressure above 60 mmHg nor prevented thesubsequent severe bronchospasm. An ECMO implantation wasrequired. Thus, even intravenous epinephrine may not providethe desired benefit in anaphylactic shock or respiratory failure.Omalizumab binds to free IgE, thus reducing mast cellactivation. The decrease in symptoms and tryptase levelsafter omalizumab should not be interpreted as a cause-effectrelationship. Omalizumab was administered after the first 5episodes of tachycardia, and the patient remained tachycardiacfor another 24 h. In patients with mastocytosis who respondto treatment, it takes a median of 1 month for symptoms toimprove (9).In conclusion, anaphylaxis in systemic mastocytosis can leadto a life-threatening event that is unresponsive to conventionaltherapy including epinephrine. Supportive therapy with ECMOfor hemodynamic shock and respiratory failure may belifesaving, and more effective therapies are needed (10).Data availability statementThe original contributions presented in the study areincluded in the article/Supplementary material, further inquiriescan be directed to the corresponding author/s.Ethics statementEthical review and approval was not required for the studyon human participants in accordance with the local legislationand institutional requirements. Written informed consent wasobtained from the patient for the publication of this case report.Author contributionsTS, MS, WS, CS, and BJ contributed to conceptionand design of the case report. JG, FE, and A-MWwrote the first draft of the manuscript. NB, EL, andGG wrote sections of the manuscript. All authorscontributed to manuscript revision, read, and approvedthe submitted version.AcknowledgmentsWe would like to thank Stephen Humphreys for providinglinguistic help and proofreading.Conflict of interestThe Medical University of Vienna has been granted a patentfor recombinant human diamine oxidase, on which BJ is listedamong the inventors.The remaining authors declare that the research wasconducted in the absence of any commercial or financialrelationships that could be construed as a potential conflictof interest.Publisher’s noteAll claims expressed in this article are solely thoseof the authors and do not necessarily represent thoseof their affiliated organizations, or those of the publisher,the editors and the reviewers. Any product that may beevaluated in this article, or claim that may be madeby its manufacturer, is not guaranteed or endorsed bythe publisher.Supplementary materialThe Supplementary Material for this article can befound online at: https://www.frontiersin.org/articles/10.3389/falgy.2022.934436/full#supplementary-materialReferences1. Valent P, Sperr WR, Schwartz LB, Horny HP. Diagnosis and classificationof mast cell proliferative disorders: delineation from immunologic diseases andnon-mast cell hematopoietic neoplasms. J Allergy Clin Immunol. (2004) 114:3–11. doi: 10.1016/j.jaci.2004.02.0452. Valent P, Akin C, Hartmann K, Nilsson G, Reiter A, HermineO, et al. Advances in the classification and treatment of mastocytosis:current status and outlook toward the future. Cancer Res. (2017)77:1261–70. doi: 10.1158/0008-5472.CAN-16-2234Frontiers in Allergy 04 frontiersin.orgGrafeneder et al. 10.3389/falgy.2022.9344363. Gulen T, Akin C, Bonadonna P, Siebenhaar F, Broesby-Olsen S, BrockowK, et al. 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H1-antihistamines for thetreatment of anaphylaxis: cochrane systematic review. Allergy. (2007) 62:830–7. doi: 10.1111/j.1398-9995.2007.01435.x8. Shaker MS, Wallace DV, Golden DBK, Oppenheimer J, Bernstein JA,Campbell RL, et al. Anaphylaxis-a 2020 practice parameter update, systematicreview, and Grading of Recommendations, Assessment, Development andEvaluation (GRADE) analysis. J Allergy Clin Immunol. (2020) 145:1082–123. doi: 10.1016/j.jaci.2020.01.0179. Lemal R, Fouquet G, Terriou L, Vaes M, Bulai Livideanu C, Frenzel L,et al. Omalizumab Therapy for Mast Cell-Mediator Symptoms in Patients withISM, CM, MMAS, and MCAS. J Allergy Clin Immunol Pract. (2019) 7:2387–95.e2383. doi: 10.1016/j.jaip.2019.03.03910. Gludovacz E, Schuetzenberger K, Resch M, Tillmann K, Petroczi K,Schosserer M, et al. Heparin-binding motif mutations of human diamine oxidaseallow the development of a first-in-class histamine-degrading biopharmaceutical.Elife. 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Multi-phasic life-threatening anaphylaxis refractory to epinephrine managed by extracorporeal membrane oxygenation (ECMO): A case report

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Multi-phasic life-threatening anaphylaxis refractory to epinephrine managed by extracorporeal membrane oxygenation (ECMO): A case report

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