Journal of Clinical Anesthesia (2014) 26, 574–576

Case Report

Anaphylaxis to succinylated gelatin in a patientwith a meat allergy: galactose-α(1, 3)-galactose(α-gal) as antigenic determinant

A. Uyttebroek MD (PhD student)a,b, V. Sabato MD (Senior Staff Member)a,b,C.H. Bridts MSc (Medical Laboratory Technician)b,L.S. De Clerck MD, PhD (Professor of Immunology Rheumatology)a,b,D.G. Ebo MD, PhD (Professor of Immunology Allergology)a,b,⁎

aFaculty of Medicine, Department of Immunology, Allergology, Rheumatology, University of Antwerp, 2610 Antwerp, BelgiumbDepartment of Immunology, Allergology, Rheumatology, Antwerp University Hospital, 2650 Antwerp, Belgium

Received 12 September 2013; revised 11 April 2014; accepted 27 April 2014

oTfa

h0

Keywords:Gelatin allergy;Perioperative anaphylaxis;α-gal allergy

Abstract Specific immunoglobulin E (sIgE) antibodies towards the galactose-α(1,3)-galactose (α-gal)moieties may elicit life-threatening and fatal anaphylactic reactions. Patients sensitized to α-gal moietiesfrom mammalian meat may also react towards mammalian gelatins and gelatin-containing drugs such asbovine gelatin-based colloid plasma substitute. The case of a 56 year old woman with a meat allergy whosuffered anaphylaxis to succinylated gelatin is reported.© 2014 Elsevier Inc. All rights reserved.

1. Introduction

Specific immunoglobulin E (sIgE) antibodies towards thegalactose-α(1,3)-galactose (α-gal) moieties coupled to theasparagine at position 88 in the murine heavy chainFab portion of the chimeric mouse-human IgG1 mAb mayelicit life-threatening and fatal anaphylactic reactions [1].Alpha-gal is synthesized by α(1, 3)-galactosyltransferase thatcouples a terminal galactose residue in an α-linkage to anothergalactose. Alpha(1,3)-galactosyltransferase displays a peculiarpattern inmammals, as its expression is suppressed in primatesincluding humans, apes, andOldWorldmonkeys [2]. Asα-gal

⁎ Correspondence: D.G. Ebo, MD, PhD, University of Antwerp, Facultyf Medicine, Immunology, Allergology, Rheumatology, Campus Drie Eiken4.08, Universiteitsplein 1, 2610 Antwerpen, Belgium. Tel.: +32 3 265 2595;x: +32 3 265 2655.

E-mail address: immuno@ua.ac.be (D.G. Ebo).

ttp://dx.doi.org/10.1016/j.jclinane.2014.04.014952-8180/© 2014 Elsevier Inc. All rights reserved.

is present on proteins of most nonprimate mammals, Chunget al. [1] also quantified sIgE to different cat, dog, beef, andpork proteins and identified several patients who had possiblysuffered from delayed anaphylaxis or serious angioedema upto 3 to 6 hours after eating beef or pork. This observation waslater confirmed by others [3–7] and it was demonstrated thatα-gal sensitization and related mammalian meat allergiescan result from tick bites [8].

2. Case report

A 56 year old woman was referred to our institution for ananaphylactic reaction with urticaria and severe bronchospasm

Table 1 Patient’s characteristics

Serum specific IgE antibodies (kUA/L)

Test α-gal Gelatin Pork Beef Chicken Lamb Horse Milk Cat dander Dog dander

Value 27.1 b0.35 6.30 5.96 b0.35 8.16 6.72 7.14 b0.35 b0.35Normal b0.35 kUA/L

IgE for casein, alfa-lactalbumin, beta-lactoglobulin, and bovine serum albumin were negative (b0.35)

Total IgE (kU/L)

Value 664 Normal 0 - 200

Skin prick test (SPT) (wheal/flare)

Test Pork ⁎ Gelofusine † Cetuximab ‡ Buffer § Histamine ║

Value 0/2 5/15 3/5 0/0 5/12Normal b3/3 mm

IgE = immunoglobulin E, IDT = intradermal testing.⁎ SPT with raw and cooked meat.† dilution series: SPT 1/1, IDT 1/10, patient tested positive on the undiluted SPT.‡ dilution series: SPT 1/1000; 1/100; 1/10; 1/1 (patient tested positive on the SPT 1/1).§ NaCl buffer (negative control).║ Histamine (positive control).

575Gelatin anaphylaxis and meat allergy

during epidural anesthesia. She had no history of atopy or anyprevious drug allergies. For several years, she had suffered fromintermittent urticaria related to consumption of dairy productsand various meat species (eg, pork and beef). These episodesappeared to be late in onset (4–6 hrs after the meal).

Review of the anesthetic record showed exposure tochlorhexidine, chloroprocaine, lidocaine, latex, and a bovinegelatin-based colloid plasma substitute (Gelofusin®, 40mg/mLgelatin; B. Braun, Melsungen AG, Germany). In Gelofusin, thepolypeptide chains are stretched and negatively charged duringa succinylation process in order to prolong its circulation.The symptoms were noticeable and they started immediatelyafter infusion of the plasma substitute. Four weeks after theacute event, allergy work-up for the mentioned medications,natural rubber latex, and chlorhexidine was performed [9].Baseline tryptase was 4.8 μg/L (normal b 11.4). Subcutaneoustests with lidocaine and chloroprocaine were negative. Thework-up was also comprised of skin prick tests (SPT) and/orquantification of serum sIgE to different mammalian meatspecies (beef, pork, horse meat, lamb), chicken meat, milk andcomponents, bovine serum albumin, and the oligosaccharidegalactose-α-1,3-galactose (α-gal). sIgE antibodies towardsα-gal were measured using a solid-phase technique. Thisassay contains bovine thyroglobulin bearing about 16 α-galmoieties/molecules and is available from Thermo FisherScientific (Uppsala, Sweden) for research use only. It is knownto have a high sensitivity for detecting anti-α-gal sIgEantibodies [3].

Furthermore, SPT with different nonirritant dilutionsof succinylated bovine gelatin (Gelofusin) and chimericmouse-human IgG1 mAb cetuximab (Erbitux®; max con-centration 5 mg/mL; Merck, Overijse, Belgium) wereperformed [7]. Skin prick tests were carried out on the

volar side of the forearm and were considered positive with awheal response exceeding 3 mm and accompanied by flare.The results are displayed inTable 1 and suggest sensitization togalactose-α (1, 3)-galactose (α-gal).

3. Discussion

Patients sensitized to α-gal moieties from mammalianmeat might react towards mammalian gelatins and gelatin-containing drugs such as bovine gelatin-based colloid plasmasubstitute [5]. It appears that the α-gal-related gelatin allergydiffers from genuine gelatin allergy and may easily beoverlooked. Patients might tolerate oral challenges with 10 gof bovine gelatin, but present with urticaria and broncho-spasm during intravenous challenges [5]. Second, diagnosisof α-gal-related gelatin sensitization and allergy may readilybe missed by a conventional gelatin sIgE assay (as observedin this patient), requiring additional skin testing [5]. Actually,correct diagnosis of an α-gal allergy starts with history takingfor mammalian meat and gelatin allergy complemented byappropriate in vitro and in vivo tests.

These comprise quantification of sIgE antibodies againstmammalian meat and determination of anti-α-gal sIgE. Skinprick tests generally involve several raw and cooked meatspecies aswell as cetuximab,which contains 10.2μgα-gal/5mg[5]. Correct diagnosis of α-gal-related gelatin sensitization andallergy seems to require skin prick or intradermal testing usingundiluted bovine gelatin-derived colloids such as Gelofusin orHaemaccel (35 mg/mL gelatin; Aventis Pharma, Paris, France)that contain 0.52 ± 0.1 μg and 0.44 ± 0.2 μg/g of α-gal,respectively [5]. Although some of the patients report symptoms

576 A. Uyttebroek et al.

to cow’s milk and all display positive sIgE results for cow’smilk, sIgE for the cow’s milk components α-lactalbumin(Bos d 4),β-globulin (Bos d 5), and casein (Bos d 8) is negative[7]. This gelatin allergy should be differentiated from genuinegelatin allergy that results from the proteinic backbone of themolecule and that is also well known to constitute a significantrisk for anesthesia [10,11].

3.1. Conclusion

An α-gal sensitized patient may suffer from immediateanaphylaxis after administration of a bovine gelatin-based colloidplasma substitute. Diagnosis of an α-gal-related gelatin allergy isreadily overlooked as patients may demonstrate negative sIgEtests for gelatin and tolerate an oral gelatin challenge.

References

[1] Chung CH, Mirakhur B, Chan E, Le Q-T, Berlin J, Morse M, Murphy B,Satinover S, Hosen J, Mauro D, Slebos R, Zhou Q, Gold D, Hatley T,Hicklin D, Platts-Mills T. Cetuximab-induced anaphylaxis and IgE specificfor galactose-alpha-1,3-galactose. N Engl J Med 2008;358:1109-17.

[2] Galili U, Shohet SB,Kobrin E, Stults CL,Macher BA.Man, apes, andOldWorld monkeys differ from other mammals in the expression of alpha-galactosyl epitopes on nucleated cells. J Biol Chem 1988;263:17755-62.

[3] Commins SP, Satinover SM, Hosen J, Mozena J, Borish L, Lewis BD,Woodfolk JA, Platts-Mills TA. Delayed anaphylaxis, angioedema, or

urticaria after consumption of red meat in patients with IgE antibodiesspecific for galactose-alpha-1,3-galactose. J Allergy Clin Immunol2009;123:426-33.

[4] Jacquenet S, Moneret-Vautrin DA, Bihain BE. Mammalian meat-induced anaphylaxis: clinical relevance of anti-galactose-alpha-1,3-galactose IgE confirmed by means of skin tests to cetuximab. J AllergyClin Immunol 2009;124:603-5.

[5] Mullins RJ, James H, Platts-Mills TA, Commins S. Relationship betweenredmeat allergy and sensitization to gelatin and galactose-α-1,3-galactose.J Allergy Clin Immunol 2012;129:1334-42.

[6] Morisset M, Richard C, Astier C, Jacquenet S, Croizier A, Beaudouin E,CordebarV,Morel-Codreanu F, Petit N,Moneret-Vautrin DA,KannyG.Anaphylaxis to pork kidney is related to IgE antibodies specific forgalactose-alpha-1,3-galactose. Allergy 2012;67:699-704.

[7] Ebo DG, Fisher M, Sabato V, Leysen J, Gadisseur A, Bridts C, DeClerck L. Sensitization to the mammalian oligosaccharide galactose-alpha-1,3-galactose (alpha-gal): experience in a Flemish case series.Acta Clin Belg 2013;68:206-9.

[8] Commins SP, James HR, Kelly LA, Pochan SL, Workman LJ,Perzanowski MS, Kocan KM, Fahy JV, Nganga LW, Ronmark E,Cooper PJ, Platts-Mills TA. The relevance of tick bites to theproduction of IgE antibodies to the mammalian oligosaccharidegalactose-α-1,3-galactose. J Allergy Clin Immunol 2011;127:1286-93.

[9] Ebo DG, Fisher MM, Hagendorens MM, Bridts CH, Stevens WJ.Anaphylaxis during anaesthesia: diagnostic approach. Allergy2007;62:471-87.

[10] Shah G, Scadding G, Nguyen-Lu N, Wigmore T, Chenzbraun A,Wechalekar K, Sharma R, Lyon AR. Peri-operative cardiac arrest withST elevation secondary to gelofusin anaphylaxis - Kounis syndrome inthe anaesthetic room. Int J Cardiol 2013;164:e22-6.

[11] Spencer HT, Hsu JT, McDonald DR, Karlin LI. Intraoperativeanaphylaxis to gelatin in topical hemostatic agents during anterior spinalfusion: a case report. Spine J 2012;12:e1-6.