Perflutren lipid microspheres for echocardiogram contrast: A clinical case of anaphylaxis to the non-PEGylated component

Perflutren lipid microspheres for echocardiogram contrast: A clinical case of anaphylaxis to the non-PEGylated component | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Perflutren lipid microspheres for echocardiogram contrast: A clinical case of anaphylaxis to the non-PEGylated component Chloe Wang, Jackie Campbell, Harriet Lea-Banks, Erika Lee This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5919930/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 May, 2025 Read the published version in Allergy, Asthma & Clinical Immunology → Version 1 posted 9 You are reading this latest preprint version Abstract Background Perflutren lipid microsphere suspension, sold under the brand name Definity®, is a microbubble ultrasound contrast agent. The microspheres contain octafluoropropane (C 3 F 8 ) gas encapsulated by an outer lipid shell of phospholipids and a polyethylene glycol (PEG)ylated phospholipid. Anaphylaxis to perflutren (Definity®) lipid microspheres is rare, with only one case report attributing the reaction to the PEG excipient. We report a novel case of anaphylaxis likely caused by a non-PEGylated component of Definity®. Case Presentation: Our patient is a healthy 54-year-old female, who underwent an exercise stress transthoracic echocardiogram using perflutren (Definity®) as an enhancing agent. She experienced anaphylaxis within 15 minutes of injection. Symptoms resolved after she was treated with diphenhydramine (Benadryl®) and epinephrine, followed by a systemic corticosteroid and ondansetron in the Emergency Department. The patient underwent allergy testing at our clinic for perflutren (Definity®) and various PEG-containing substances. While all PEG products tested negative, she had a positive intradermal test to perflutren. She also passed an oral challenge to PEG 3350, thus ruling out PEG as the causative agent of anaphylaxis. Conclusions Our case report highlights a previously undocumented instance of IgE-mediated anaphylaxis to Definity® with a non-PEGylated component as the likely culprit. It provides critical information to physicians on the potential risks of using Definity® and contributes to growing research surrounding the profile of Definity®. perflutren lipid microspheres ultrasound contrast agent echocardiogram contrast agent anaphylaxis PEG polyethylene glycol IgE-mediated reaction Figures Figure 1 Background Perflutren lipid microsphere suspension, sold under the brand name Definity®, is a microbubble ultrasound contrast agent (UCA) widely used across North America and the only UCA marketed in Canada. Injected intravenously, its physical acoustic properties allow delineation of the inner border of the left ventricle of the heart, which clarifies images during echocardiograms. Upon activation, the microspheres are made of octafluoropropane (C 3 F 8 ) gas encapsulated by an outer lipid shell, consisting of phospholipids and a PEGylated phospholipid (MPEG5000 DPPE) with an approximate molecular weight (MW) of 5750. 1 , 2 Anaphylactoid reactions to Definity® are rare 3 and only one case report of anaphylaxis was found, which was attributed to polyethylene glycol (PEG). 4 Case Presentation We report a novel case of anaphylaxis to the non-PEGylated component of Definity®. Our patient is a healthy 54-year-old female, who underwent an exercise stress transthoracic echocardiogram at her cardiologist’s office, using perflutren as an enhancing agent. Within 15 minutes after injection and while walking on a treadmill, she developed urticaria on her arms that spread to the torso, followed by syncope. Upon arousal, she experienced emesis, urinary incontinence, tongue swelling, and dyspnea. She was treated with diphenhydramine (Benadryl®) intravenously, and paramedics later gave her epinephrine. She also received a systemic corticosteroid and ondansetron while in the ED, where her symptoms resolved after several hours. The patient came to our drug allergy clinic one month later and underwent skin prick testing (SPT) to PEG 3350 and intradermal testing (IDT) to activated Definity® (agitated with Vialmix® to form lipid-shell octafluoropropane microbubbles), methylprednisolone acetate (Depo-Medrol®, which contains PEG 3350) and methylprednisolone sodium succinate (Solu-Medrol®, which does not contain PEG 3350, as a control). Following negative SPT and IDT to PEG, she proceeded to a two-step oral challenge with PEG 3350 (Lax-A-Day®) to a cumulative dose of 17 grams. She remained under observation for more than 1 hour without evidence of an immediate allergic reaction. However, the patient had a positive IDT to perflutren (Definity®) at both 1:100 and 1:10 dilutions, with the injection sites becoming indurated with surrounding erythema and expanding outside the IDT sites 15 minutes after administration (Fig. 1 ). On a separate day, she underwent SPT to PEG 8000 with negative results. Based on the testing outcomes, we concluded that she had an IgE-mediated reaction to a non-PEGylated component of the perflutren contrast agent. Discussion and Conclusions Polyethylene glycols, also known as macrogols, are hydrophilic molecules that are often used in medical, pharmaceutical, and cosmetic products. They are available in a range of molecular weights from 200 to 35,000 g/mol with PEG 3350 as a common ingredient in laxatives and bowel preparations. 4 PEG derivatives are structurally similar polymers and are often used as drug excipients, 5 as is the case for Definity® microspheres. Many severe immediate-type hypersensitivity reactions have been reported following the use of PEG 4000, 6000, 8000 and 20,000, 6 and in reports between 1989 and 2017, the US FDA identified 53 cases of anaphylactic reactions to bowel preparations or laxatives containing PEG. 5 However, anaphylaxis to PEGylated products such as Definity® has been rare overall. In a retrospective analysis, more than 66,000 administered doses of Definity® over a period of 4.5 ± 2.4 years were analyzed, of which only 8 serious adverse events were reported as probably related to Definity®. Of these, 4 were described as anaphylactic, with symptoms including hypotension, dyspnea, urticaria, and swelling of the face and throat. They all occurred within 15 minutes of administration and patients recovered after 4 to 8 hours in the hospital after being treated with fluids, antihistamines, steroids, and/or epinephrine. Thus, the incidence of anaphylaxis to Definity® was recorded to be 0.006%, 3 although confirmatory allergy testing was not performed; thus, the mechanism(s) of the reactions were not determined. To our knowledge, there is only one case report of an anaphylactic reaction to Definity®, with the culprit being the PEGylated part of the microsphere. The patient was a 58-year-old male who, within minutes of being given Definity® for a stress myocardial perfusion scan, developed urticaria, shortness of breath, and hypotension. Previously, he had developed swollen hands when handling paints containing high molecular weight PEG and anaphylaxis to oral PEG 3350 during preparation for a colonoscopy. He later tested positive on SPT to PEG 3350 and methylprednisolone acetate (containing PEG), and positive on IDT to triamcinolone acetonide (containing polysorbate 80). It was concluded that his immediate reactions to the PEG products and Definity® were due to an IgE-mediated reaction to PEG. 4 On the other hand, our patient had a positive IDT to perflutren (Definity®) but not to PEG-containing medications, and tolerated an oral challenge to PEG 3350. She also tested negative for PEG 8000 SPT, deeming the higher molecular weight PEG 5750 in Definity® to be an unlikely culprit. Definity® contains excipients in the buffer such as glycerin and propylene glycol which are often considered immunologically inert. 2 Thus, we suspect that the patient likely experienced anaphylaxis to a non-PEGylated component of perflutren contrast agent. Of note, our patient had exercise as a cofactor, which could have contributed to the severe presentation. In summary, immediate hypersensitivity reactions to Definity® are rare, with most reported cases attributing PEG as the likely allergen. We present the first documented case of an IgE-mediated reaction potentially triggered by a non-PEG component of Definity®. This case highlights a new response to Definity® unrelated to the PEG excipient and the importance of physicians to be aware of this rare but critical situation. Abbreviations UCA – ultrasound contrast agent; MW – molecular weight; PEG – polyethylene glycol; SPT – skin prick test; IDT – intradermal test Declarations Ethics approval and consent to participate: Not applicable. Consent for publication: A consent form was signed by the patient to report the case. Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests: The authors declare that they have no competing interests. Funding: None Authors' contributions: CW drafted the report and conducted preliminary background research. JC provided pharmacological details on the drugs used in testing. HL provided information and research on Definity®. EL performed drug allergy testing on the patient, interpreted results, and provided patient records. All authors revised, reviewed and approved the final manuscript. Acknowledgements: We thank the Echocardiography team at Sunnybrook Health Sciences Centre for their assistance in activating Definity®. References Lantheus Medical Imaging. Definity: Prescribing Information. Massachusetts: Lantheus Medical Imaging; 2024. https://www.definityimaging.com/sites/default/files/pdf/definity-pi.pdf. Accessed 30 Nov 2024. Lantheus MI Canada. Definity: Product Monograph. Montreal: Lantheus MI Canada; 2022. https://pdf.hres.ca/dpd_pm/00067309.PDF. Accessed 30 Nov 2024. Wei K, Mulvagh SL, Carson L, Davidoff R, Gabriel R, Grimm RA, et al. The Safety of Definity and Optison for Ultrasound Image Enhancement: A Retrospective Analysis of 78,383 Administered Contrast Doses. J Am Soc Echocardiogr. 2008;21(11):1202-1206. doi:10.1016/j.echo.2008.07.019. Krantz MS, Liu Y, Phillips EJ, Stone CA Jr. Anaphylaxis to PEGylated liposomal echocardiogram contrast in a patient with IgE-mediated macrogol allergy. J Allergy Clin Immunol Pract. 2020;8(4):1416-1419.e3. doi:10.1016/j.jaip.2019.12.041. Stone CA, Liu Y, Relling MV, Krantz MS, Pratt AL, Abreo A, et al. Immediate Hypersensitivity to Polyethylene Glycols and Polysorbates: More Common Than We Have Recognized. J Allergy Clin Immunol Pract. 2019;7(5):1533-1540.e8. doi:10.1016/j.jaip.2018.12.003. Caballero ML, Krantz MS, Quirce S, Phillips EJ, Stone CA. Hidden Dangers: Recognizing Excipients as Potential Causes of Drug and Vaccine Hypersensitivity Reactions. J Allergy Clin Immunol Pract. 2021;9(8):2968-2982. doi:10.1016/j.jaip.2021.03.002. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 07 May, 2025 Read the published version in Allergy, Asthma & Clinical Immunology → Version 1 posted Editorial decision: Revision requested 13 Feb, 2025 Reviews received at journal 13 Feb, 2025 Reviewers agreed at journal 13 Feb, 2025 Reviews received at journal 13 Feb, 2025 Reviewers agreed at journal 06 Feb, 2025 Reviewers invited by journal 03 Feb, 2025 Editor assigned by journal 29 Jan, 2025 Submission checks completed at journal 29 Jan, 2025 First submitted to journal 28 Jan, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5919930","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":408604218,"identity":"8255d7e3-d2cc-48ac-bf36-8c2e42ed7f11","order_by":0,"name":"Chloe Wang","email":"","orcid":"","institution":"Western University","correspondingAuthor":false,"prefix":"","firstName":"Chloe","middleName":"","lastName":"Wang","suffix":""},{"id":408604219,"identity":"6e94b580-311b-4aa2-91e3-5cdb86acf120","order_by":1,"name":"Jackie Campbell","email":"","orcid":"","institution":"Sunnybrook Health Sciences Centre","correspondingAuthor":false,"prefix":"","firstName":"Jackie","middleName":"","lastName":"Campbell","suffix":""},{"id":408604220,"identity":"d91526b9-ef0d-4678-83a2-f000a2cfddb7","order_by":2,"name":"Harriet Lea-Banks","email":"","orcid":"","institution":"Sunnybrook Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Harriet","middleName":"","lastName":"Lea-Banks","suffix":""},{"id":408604221,"identity":"d836e9ad-18ce-429c-bda9-aa93cc5acb93","order_by":3,"name":"Erika Lee","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBklEQVRIie2OMUsDMRSA31HwlidZ31GtfyElS4eAfyVBuO1At24KAW85dS34JwoHXXtS0OW6W1wqN+rgeIODr1aUSqgdHfINSQjv43sAgcC/JHJ8DADiCwBzurtCAFixIvn+/DVbnc5aodXULorozpxsgXoiebFvSwl2Gl89N2etBpFXXiW5ts4WQCq5zUrixWyBD0qNTApU+1OyjlyFQHb8lI3XCqV7XTQzXtKvHLNy9w50Pl3My3ZTEUt/BSN3whUjaX/yq0L+CnFFHUjqj+psMmBRFfV9R2GaIj36K6KIm+R1qI9EPi8X7VAf5vll1KDWPXHjr3yt91P9fuGW+UAgEAj8wQdYeFAwbbbdTwAAAABJRU5ErkJggg==","orcid":"","institution":"Sunnybrook Health Sciences Centre","correspondingAuthor":true,"prefix":"","firstName":"Erika","middleName":"","lastName":"Lee","suffix":""}],"badges":[],"createdAt":"2025-01-28 16:53:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5919930/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5919930/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13223-025-00964-5","type":"published","date":"2025-05-07T15:56:54+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":75188637,"identity":"efb9cb29-1ceb-4068-b1e7-2df25558a508","added_by":"auto","created_at":"2025-01-31 18:01:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":3632632,"visible":true,"origin":"","legend":"\u003cp\u003eSkin testing results. The patient had appropriate responses to SPT controls. She tested negative for serial dilutions of PEG 3350 SPT. On IDT, she was only positive to perflutren (Definity®; both concentrations) at 15-minute read. On a separate day, SPT to PEG 8000 (5 mL dissolved in 10mL saline) was negative (results not shown).\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5919930/v1/7043b33d8261de6012dfafc4.png"},{"id":82537571,"identity":"ac6f7af5-6a2a-4487-9013-6327f93c5bc3","added_by":"auto","created_at":"2025-05-12 16:08:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4691024,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5919930/v1/3a253b69-a56a-4b37-81a9-476f5e860084.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Perflutren lipid microspheres for echocardiogram contrast: A clinical case of anaphylaxis to the non-PEGylated component","fulltext":[{"header":"Background","content":"\u003cp\u003ePerflutren lipid microsphere suspension, sold under the brand name Definity\u0026reg;, is a microbubble ultrasound contrast agent (UCA) widely used across North America and the only UCA marketed in Canada. Injected intravenously, its physical acoustic properties allow delineation of the inner border of the left ventricle of the heart, which clarifies images during echocardiograms. Upon activation, the microspheres are made of octafluoropropane (C\u003csub\u003e3\u003c/sub\u003eF\u003csub\u003e8\u003c/sub\u003e) gas encapsulated by an outer lipid shell, consisting of phospholipids and a PEGylated phospholipid (MPEG5000 DPPE) with an approximate molecular weight (MW) of 5750.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Anaphylactoid reactions to Definity\u0026reg; are rare\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e and only one case report of anaphylaxis was found, which was attributed to polyethylene glycol (PEG).\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eWe report a novel case of anaphylaxis to the non-PEGylated component of Definity®. Our patient is a healthy 54-year-old female, who underwent an exercise stress transthoracic echocardiogram at her cardiologist’s office, using perflutren as an enhancing agent. Within 15 minutes after injection and while walking on a treadmill, she developed urticaria on her arms that spread to the torso, followed by syncope. Upon arousal, she experienced emesis, urinary incontinence, tongue swelling, and dyspnea. She was treated with diphenhydramine (Benadryl®) intravenously, and paramedics later gave her epinephrine. She also received a systemic corticosteroid and ondansetron while in the ED, where her symptoms resolved after several hours.\u003c/p\u003e \u003cp\u003eThe patient came to our drug allergy clinic one month later and underwent skin prick testing (SPT) to PEG 3350 and intradermal testing (IDT) to activated Definity® (agitated with Vialmix® to form lipid-shell octafluoropropane microbubbles), methylprednisolone acetate (Depo-Medrol®, which contains PEG 3350) and methylprednisolone sodium succinate (Solu-Medrol®, which does not contain PEG 3350, as a control). Following negative SPT and IDT to PEG, she proceeded to a two-step oral challenge with PEG 3350 (Lax-A-Day®) to a cumulative dose of 17 grams. She remained under observation for more than 1 hour without evidence of an immediate allergic reaction. However, the patient had a positive IDT to perflutren (Definity®) at both 1:100 and 1:10 dilutions, with the injection sites becoming indurated with surrounding erythema and expanding outside the IDT sites 15 minutes after administration (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). On a separate day, she underwent SPT to PEG 8000 with negative results. Based on the testing outcomes, we concluded that she had an IgE-mediated reaction to a non-PEGylated component of the perflutren contrast agent.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e "},{"header":"Discussion and Conclusions","content":"\u003cp\u003ePolyethylene glycols, also known as macrogols, are hydrophilic molecules that are often used in medical, pharmaceutical, and cosmetic products. They are available in a range of molecular weights from 200 to 35,000 g/mol with PEG 3350 as a common ingredient in laxatives and bowel preparations.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e PEG derivatives are structurally similar polymers and are often used as drug excipients,\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e as is the case for Definity® microspheres. Many severe immediate-type hypersensitivity reactions have been reported following the use of PEG 4000, 6000, 8000 and 20,000,\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e and in reports between 1989 and 2017, the US FDA identified 53 cases of anaphylactic reactions to bowel preparations or laxatives containing PEG.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e However, anaphylaxis to PEGylated products such as Definity® has been rare overall. In a retrospective analysis, more than 66,000 administered doses of Definity® over a period of 4.5 ± 2.4 years were analyzed, of which only 8 serious adverse events were reported as probably related to Definity®. Of these, 4 were described as anaphylactic, with symptoms including hypotension, dyspnea, urticaria, and swelling of the face and throat. They all occurred within 15 minutes of administration and patients recovered after 4 to 8 hours in the hospital after being treated with fluids, antihistamines, steroids, and/or epinephrine. Thus, the incidence of anaphylaxis to Definity® was recorded to be 0.006%,\u003csup\u003e3\u003c/sup\u003e although confirmatory allergy testing was not performed; thus, the mechanism(s) of the reactions were not determined.\u003c/p\u003e\u003cp\u003eTo our knowledge, there is only one case report of an anaphylactic reaction to Definity®, with the culprit being the PEGylated part of the microsphere. The patient was a 58-year-old male who, within minutes of being given Definity® for a stress myocardial perfusion scan, developed urticaria, shortness of breath, and hypotension. Previously, he had developed swollen hands when handling paints containing high molecular weight PEG and anaphylaxis to oral PEG 3350 during preparation for a colonoscopy. He later tested positive on SPT to PEG 3350 and methylprednisolone acetate (containing PEG), and positive on IDT to triamcinolone acetonide (containing polysorbate 80). It was concluded that his immediate reactions to the PEG products and Definity® were due to an IgE-mediated reaction to PEG.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eOn the other hand, our patient had a positive IDT to perflutren (Definity®) but not to PEG-containing medications, and tolerated an oral challenge to PEG 3350. She also tested negative for PEG 8000 SPT, deeming the higher molecular weight PEG 5750 in Definity® to be an unlikely culprit. Definity® contains excipients in the buffer such as glycerin and propylene glycol which are often considered immunologically inert.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Thus, we suspect that the patient likely experienced anaphylaxis to a non-PEGylated component of perflutren contrast agent. Of note, our patient had exercise as a cofactor, which could have contributed to the severe presentation.\u003c/p\u003e\u003cp\u003eIn summary, immediate hypersensitivity reactions to Definity® are rare, with most reported cases attributing PEG as the likely allergen. We present the first documented case of an IgE-mediated reaction potentially triggered by a non-PEG component of Definity®. This case highlights a new response to Definity® unrelated to the PEG excipient and the importance of physicians to be aware of this rare but critical situation.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eUCA \u0026ndash; ultrasound contrast agent; MW \u0026ndash; molecular weight; PEG \u0026ndash; polyethylene glycol; SPT \u0026ndash; skin prick test; IDT \u0026ndash; intradermal test\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e A consent form was signed by the patient to report the case.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e None\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u003c/strong\u003e CW drafted the report and conducted preliminary background research. JC provided pharmacological details on the drugs used in testing. HL provided information and research on Definity\u0026reg;. EL performed drug allergy testing on the patient, interpreted results, and provided patient records. All authors revised, reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e We thank the Echocardiography team at Sunnybrook Health Sciences Centre for their assistance in activating Definity\u0026reg;.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eLantheus Medical Imaging. Definity: Prescribing Information. Massachusetts: Lantheus Medical Imaging; 2024. https://www.definityimaging.com/sites/default/files/pdf/definity-pi.pdf. Accessed 30 Nov 2024.\u003c/li\u003e\n \u003cli\u003eLantheus MI Canada. Definity: Product Monograph. Montreal: Lantheus MI Canada; 2022. https://pdf.hres.ca/dpd_pm/00067309.PDF. Accessed 30 Nov 2024.\u003c/li\u003e\n \u003cli\u003eWei K, Mulvagh SL, Carson L, Davidoff R, Gabriel R, Grimm RA, et al. The Safety of Definity and Optison for Ultrasound Image Enhancement: A Retrospective Analysis of 78,383 Administered Contrast Doses. J Am Soc Echocardiogr. 2008;21(11):1202-1206.\u0026nbsp;doi:10.1016/j.echo.2008.07.019.\u003c/li\u003e\n \u003cli\u003eKrantz MS, Liu Y, Phillips EJ, Stone CA Jr. Anaphylaxis to PEGylated liposomal echocardiogram contrast in a patient with IgE-mediated macrogol allergy. J Allergy Clin Immunol Pract. 2020;8(4):1416-1419.e3.\u0026nbsp;doi:10.1016/j.jaip.2019.12.041.\u003c/li\u003e\n \u003cli\u003eStone CA, Liu Y, Relling MV, Krantz MS, Pratt AL, Abreo A, et al. Immediate Hypersensitivity to Polyethylene Glycols and Polysorbates: More Common Than We Have Recognized. J Allergy Clin Immunol Pract. 2019;7(5):1533-1540.e8. doi:10.1016/j.jaip.2018.12.003.\u003c/li\u003e\n \u003cli\u003eCaballero ML, Krantz MS, Quirce S, Phillips EJ, Stone CA. Hidden Dangers: Recognizing Excipients as Potential Causes of Drug and Vaccine Hypersensitivity Reactions. J Allergy Clin Immunol Pract. 2021;9(8):2968-2982. doi:10.1016/j.jaip.2021.03.002.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"allergy-asthma-and-clinical-immunology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aaci","sideBox":"Learn more about [Allergy, Asthma \u0026 Clinical Immunology](http://aacijournal.biomedcentral.com/)","snPcode":"13223","submissionUrl":"https://submission.nature.com/new-submission/13223/3","title":"Allergy, Asthma \u0026 Clinical Immunology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"perflutren lipid microspheres, ultrasound contrast agent, echocardiogram contrast agent, anaphylaxis, PEG, polyethylene glycol, IgE-mediated reaction","lastPublishedDoi":"10.21203/rs.3.rs-5919930/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5919930/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePerflutren lipid microsphere suspension, sold under the brand name Definity\u0026reg;, is a microbubble ultrasound contrast agent. The microspheres contain octafluoropropane (C\u003csub\u003e3\u003c/sub\u003eF\u003csub\u003e8\u003c/sub\u003e) gas encapsulated by an outer lipid shell of phospholipids and a polyethylene glycol (PEG)ylated phospholipid. Anaphylaxis to perflutren (Definity\u0026reg;) lipid microspheres is rare, with only one case report attributing the reaction to the PEG excipient. We report a novel case of anaphylaxis likely caused by a non-PEGylated component of Definity\u0026reg;.\u003c/p\u003e\u003ch2\u003eCase Presentation:\u003c/h2\u003e \u003cp\u003eOur patient is a healthy 54-year-old female, who underwent an exercise stress transthoracic echocardiogram using perflutren (Definity\u0026reg;) as an enhancing agent. She experienced anaphylaxis within 15 minutes of injection. Symptoms resolved after she was treated with diphenhydramine (Benadryl\u0026reg;) and epinephrine, followed by a systemic corticosteroid and ondansetron in the Emergency Department. The patient underwent allergy testing at our clinic for perflutren (Definity\u0026reg;) and various PEG-containing substances. While all PEG products tested negative, she had a positive intradermal test to perflutren. She also passed an oral challenge to PEG 3350, thus ruling out PEG as the causative agent of anaphylaxis.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur case report highlights a previously undocumented instance of IgE-mediated anaphylaxis to Definity\u0026reg; with a non-PEGylated component as the likely culprit. It provides critical information to physicians on the potential risks of using Definity\u0026reg; and contributes to growing research surrounding the profile of Definity\u0026reg;.\u003c/p\u003e","manuscriptTitle":"Perflutren lipid microspheres for echocardiogram contrast: A clinical case of anaphylaxis to the non-PEGylated component","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-31 18:01:48","doi":"10.21203/rs.3.rs-5919930/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-02-13T18:54:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-02-13T18:52:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"77292215794445983806836941670366811206","date":"2025-02-13T18:50:01+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-02-13T16:43:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"332395131165617854865845863659685870562","date":"2025-02-06T11:04:13+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-02-04T03:23:30+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-01-29T09:14:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-01-29T09:14:17+00:00","index":"","fulltext":""},{"type":"submitted","content":"Allergy, Asthma \u0026 Clinical Immunology","date":"2025-01-28T16:47:03+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"allergy-asthma-and-clinical-immunology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aaci","sideBox":"Learn more about [Allergy, Asthma \u0026 Clinical Immunology](http://aacijournal.biomedcentral.com/)","snPcode":"13223","submissionUrl":"https://submission.nature.com/new-submission/13223/3","title":"Allergy, Asthma \u0026 Clinical Immunology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"37501f70-3af0-41ee-b6dd-28f9bc054d24","owner":[],"postedDate":"January 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-12T16:03:48+00:00","versionOfRecord":{"articleIdentity":"rs-5919930","link":"https://doi.org/10.1186/s13223-025-00964-5","journal":{"identity":"allergy-asthma-and-clinical-immunology","isVorOnly":false,"title":"Allergy, Asthma \u0026 Clinical Immunology"},"publishedOn":"2025-05-07 15:56:54","publishedOnDateReadable":"May 7th, 2025"},"versionCreatedAt":"2025-01-31 18:01:48","video":"","vorDoi":"10.1186/s13223-025-00964-5","vorDoiUrl":"https://doi.org/10.1186/s13223-025-00964-5","workflowStages":[]},"version":"v1","identity":"rs-5919930","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5919930","identity":"rs-5919930","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}