Letters / Ann Allergy Asthma Immunol 113 (2014) 321e331324

Hospital Universitario Central de AsturiasOviedo, Spain

yServicio de InmunologíaIIS-Fundación Jimenez Díaz

Universidad Autónoma de MadridMadrid, Spain

julian.azofra@sespa.princast.es

References

[1] Sicherer SH, SampsonHA. Foodallergy. J Allergy Clin Immunol. 2010;125(suppl 2):S116eS125.

[2] Griesmeier U, Vázquez-Cortés S, Bublin M, et al. Expression levels of parval-bumins determine allergenicity of fish species. Allergy. 2010;65:191e198.

Disclosure: The authors have nothing to disclose.

[3] Pérez-Gordo M, Pastor Vargas C, Cases B, et al. New allergen involved in a caseof allergy to Solea solea, common sole fish. Ann Allergy Asthma Immunol. 2010;104:352e353.

[4] Pastor C, Cuesta-Herranz J, Cases B, et al. Identification of major allergens inwatermelon. Int Arch Allergy Immunol. 2009;149:291e298.

[5] Múgica MV, Añibarro B, Seoane FJ, Lombardero M. Contact urticaria by anglerfish. Allergy. 2003;58:682e683.

[6] Kuehn A, Hilger C, Lehners-Weber C, et al. Identification of enolases and al-dolases as important fish allergens in cod, salmon and tuna: componentresolved diagnosis using parvalbumin and the new allergens. Clin Exp Allergy.2013;43:811e822.

[7] Rhosmilah M, Shahnaz M, Meinir J, Masita A, Noormalin A, Jamaluddin M.Identification of parvalbumin and two new thermolabile major allergens ofThunnus tonggol using a proteomics approach. Int Arch Allergy Immunol. 2013;162:299e309.

[8] Tomm JM, van Do T, Jende C, et al. Identification of new potential allergens fromNile perch (Lates niloticus) and cod (Gadus morhua). J Investig Allergol ClinImmunol. 2013;23:159e167.

Delayed clavulanic acideinduced anaphylaxis in a patient undergoingbariatric surgery

Selective allergy to clavulanic acid is rare, although amoxicilline precautions, including electrocardiographic monitoring, 2 IV

clavulanic acid is used frequently.1,2 With the increasing prevalenceof obesity worldwide, the number of bariatric operations hassignificantly increased in the past decade. Despite the lack of pro-spective data fromwell-controlled randomized trials, evidence fromcase reports and case series have revealed that absorption, first-passmetabolism, volume of distribution, and half-life of drugs may all bealtered after bariatric surgery in a drug-dependent manner.3,4

Occurrence of delayed anaphylaxis after oral drug challenge hasnot been reported after bariatric operations. In this article, wereport, for the first time to our knowledge, a delayed anaphylaxisthat occurred 4 hours after drug provocation using clavulanic acid ina patient undergoing sleeve gastrectomy (SG).

A 25-year-old man who had undergone SG 1 year earlier pre-sented to the emergency department (ED) with dizziness and dete-rioration of level of consciousness occurring a few hours afteringestion of amoxicillineclavulanic acid, 500/125-mg tablet taken foracute pharyngitis. In the ED, hewas drowsy, pale, and sweaty. He hada pulse rate of 140/min, blood pressure of 70/30mmHg, temperatureof 37.8�C, and respiratory rate of 36/min. Physical examinationrevealed a congested throat. His arterial blood gas on room airrevealed pH 7.18, PCO2 of 43.5 mm Hg, PO2 of 40.6 mm Hg, and bi-carbonate level of 16 mEq/L. The patient was intubated, resuscitatedwith intravenous (IV) fluids, given IV noradrenaline, and admittedto the intensive care unit. Then IV meropenem was prescribed forthe possibility of septic shock. He made a good recovery andwas discharged home on the seventh daywith a diagnosis of septicshock; however, the results of septic workup were negative. Oneweek later, 2 to 3 hours after receiving one tablet of amox-icillineclavulanic acid, 500/125 mg, and ibuprofen, 400 mg, forsore throat, he developed severe breathlessness and dizziness andwas brought to the ED hypotensive, treated as anaphylaxis withrepeated IM epinephrine administration, and discharged home 2days later. He had no rash or angioedema observed during bothpresentations. Two months later, he attended the allergy unit. Al-lergy skin prick and intradermal test results were negative forbenzylpenicilloyl-polylysine, minor determinant mixture, andamoxicillin, all provided by Diater (Madrid, Spain). Oral challengewith amoxicillin, 500mg,was tolerated. Skinprick and intradermaltests using amoxicillineclavulanic acid, 1,000/200-mg solution(SmithKline Beecham Plc, Worthing, United Kingdom) at dilutionsof 1:100, 1:10, and 1:1, were negative. Oral challenge with amox-icillineclavulanic acid, 500/125 mg, was performed with extreme

catheters in place, ready availability of emergency medications,and facilities for tracheal intubation. Hewas discharged home after3 hours without any reaction; however, 4 hours after the amox-icillineclavulanic acid challenge, he presented with dizziness andbreathlessness and collapsed in the ED. He was treated foranaphylaxis and received 3 intramuscular doses of 0.5 mg ofepinephrine, kept 24 hours under observation, discharged homewith a medical alert, and instructed to avoid clavulanic acidecontaining medications. The patient tolerated nonsteroidal anti-inflammatory drugs afterward.

Amoxicillineclavulanic acid is awidely used antibiotic composedof amoxicillin and a potent b-lactamase inhibitor (clavulanic acid).2

Type 1 hypersensitivity reactions to amoxicillineclavulanic acidcould occur because of a b-lactam ring, the R-group side chain ofamoxicillin, or the clavulanic acid molecule. Amoxicillin is thepenicillin most frequently involved in sensitization, with the sidechain playing a relevant role.5 Anaphylaxis typically developswithinminutes after exposure to the offending drug but may occasionallyoccur as late as 1 hour after exposure.6 Sanchez-Morillas and Pérez-Ezquerra1 described 9 patients with selective adverse reactions toclavulanic acid. Only 1 patient had anaphylaxis, which occurredwithin 45 minute of exposure.

Fernandez-Rivas et al2 reported 2 cases of anaphylaxis, whichoccured 40 and 10 minutes after the intake of the first capsule ofamoxicillineclavulanic acid, respectively. In both patients, the re-sults of skin tests with penicillin and amoxicillin were negative butpositive with clavulanic acid.

Bariatric operations may affect drug absorption and its bioavail-ability through different ways. The smaller volume of the stomachresults in reduced gastric mixing that may prevent adequate tabletdisintegration. The reduction of gastric acid production (higher pH)may decrease the absorption of some medications. Delayed gastricemptying is another postulated mechanism.7 Fallatah et al8 foundthat gastric emptying after SG is variable according to the point ofstarting SG from the pylorus. At 4 cm it is associated with delayedgastric emptying, and at 7 cm it is associated with acceleratedemptying for solids.

Our patient presented with 2 episodes of delayed anaphylaxisafter ingestion of amoxicillineclavulanic acid. In the first event, thediagnosis of anaphylaxiswasmissedbecause of thepresenceof fever,absence of rash, and lack of information given to the ED physicianabout ingestion of amoxicillineclavulanic acid. In the second pre-sentation, thepatient sought care in theED2 to3 tohoursafter takingamoxicillineclavulanic acid, was treated for anaphylaxis, tested

Letters / Ann Allergy Asthma Immunol 113 (2014) 321e331 325

negative for penicillin, amoxicillin, and amoxicillineclavulanic acid,and tolerated oral challenge with amoxicillin. Oral challenge withamoxicillineclavulanic acid revealed no reaction after 2 hours;however, anaphylaxis occurred 4 hours after challenge. The precisechallenge proceduremay varya lot fromone allergy team to another,and the need to standardize its practice has not been met so far9;however, observation of the patient for 2 hours after oral challengewith a full dose of a drug is adequate and acceptable bymany allergyspecialists. Occurrence of delayed anaphylaxis in our patient raisedthe question of whether bariatric surgery has a role in the delayedoccurrence of anaphylaxis. This question needs to be answered, andmore studies are needed to address this issue, especially with thenew era of increasing different bariatric operations.

Delayed anaphylaxis after ingestion of clavulanic acid is unusual;however, no literature report of delayed clavulanic acideinducedanaphylaxis similar to our case is available. We think our case reportdelivers the following messages:

1. Physicians and allergy specialists caring for patients undergoingbariatric surgery should be aware of the delayed anaphylacticreactions from drugs, specifically the antibiotics.

2. The mechanism of anaphylaxis in these patients may or may notbe different, but the absorption of drugs seems to be the issueand requires more studies.

3. We encourage physicians to report anaphylactic and otherallergic reactions in patients undergoing bariatric operations tohave further idea about these reactions.

Disclosure: Authors have nothing to disclose.

Hassan Mobayed, MDWanis Ibrahim, MD

Maryam Al-Nesf, MDDepartment of MedicineHamad General Hospital

Doha, Qatarhmobayedh@hmc.org.qa

References

[1] Sánchez-Morillas L, Pérez-Ezquerra PR. Selective allergic reactions to clavulanicacid: report of 9 cases. J Allergy Clin Immunol. 2010;126:177e179.

[2] Fernandez-Rivas M, Perez Carral C, Cuevas M, Marti C, Moral A, Senent CJ.Selective allergic reactions to clavulanic acid. J Allergy Clin Immunol. 1995;95:748e750.

[3] Sawaya R, Jaffe J, Friedenberg L, Friedenberg FK. Vitamin, mineral, and drugabsorption following bariatric surgery. Curr Drug Metab. 2012;13:1345e1355.

[4] Malone M. Altered drug disposition in obesity and after bariatric surgery. NutrClin Pract. 2003;18(2):131e135.

[5] Antúnez C, Martin E, Cornejo-Garcia JA, et al. Immediate hypersensitivity re-actions to penicillins and other betalactams. Curr Pharm Des. 2006;12:3327e3333.

[6] Kim H, Fischer D. Anaphylaxis. Allergy Asthma Clin Immunol. 2011;7(suppl 1):S6.[7] Padwal R, Brocks D, Sharma A. A systematic review of drug absorption

following bariatric surgery and its theoretical implications. Obes Rev. 2010;11:41e50.

[8] Fallatah B, Shehry AA. Comparison study of gastric emptying after performingsleeve gastrectomy with two different techniques. J Surg. 2013;1:53e56.

[9] Chiriac AM, Demoly P. Drug provocation tests: up-date and novel approaches.Allergy Asthma Clini Immunol. 2013;9:12.

Successful desensitization with anakinra in a case with immediatehypersensitivity reaction

Familial Mediterranean fever is an autosomal recessive inflamma- Skin prick test results with undiluted drug were negative,

tory disease for which colchicine is the primary treatment.1e3

Nevertheless, in patients in whom colchicine treatment is notsuccessful or leads to side effects, interleukin-1 antagonists areused as a novel treatment approach.3 Anakinra (Kineret; Sobi, Inc,Stockholm, Sweden) is a recombinant form of human interleukin-1receptor antagonist. Although it is generally safe and toleratedwell,the most important side effect is local skin reaction at the injectionsite.4 Systemic reactions to anakinra have been reported rarely.5,6

The present report describes the case of a 25-year-old womanwho presented with urticaria and angioedema in reaction to ana-kinra treatment and underwent successful desensitization.

A 25-year-old woman was referred to our allergy clinic foranakinra-related urticaria and angioedema. She was diagnosedwith familial Mediterranean fever in 2001 and had been oncolchicine since then. Daily subcutaneous anakinra injections(100 mg/d) were commenced 6 months previously for nephropa-thy. After the 12th dose, an erythematous rash with edemaoccurred locally at the injection site 4 hours after injection, whichwas resolved by oral antihistamine. Therefore, an oral antihista-minic was given before each injection, which helped the patienttolerate the anakinra for further injections. However, because shewas planning to become pregnant, anakinra was discontinued.Treatment with colchicine was continued. However, proteinuriaincreased, and anakinra was reintroduced and safely given for 19subsequent doses. However, 4 hours after the 20th dose, urticariaand angioedema developed on the face and diffuse erythemadeveloped over the entire body, which responded well to oralantihistamine. Then, the patient was referred to our clinic forevaluation of possible desensitization to anakinra.

whereas positivity was observed by intradermal tests at 1/10-folddilution. The same concentration in the intradermal test yieldednegative responses in 3 healthy controls. Therefore, the reaction ofthe patient was regarded as a type I hypersensitivity reaction toanakinra and desensitization was planned. A signed informed con-sent was obtained. Premedication with 10 mg of cetirizine orally 1hour before desensitization was administered. Because no pre-determinedprotocol for an immediate reaction to anakinra existed, anew desensitization protocol was established. For desensitization, 210-fold dilutions (1/10 and 1/100) were prepared. The initial con-centration of anakinra selected for desensitization was 1/100 of thetherapeutic dose (100mg) because the patient’s reaction historywasmild (diffuse erythema, urticaria without dyspnea, and hypoten-sion). Initially, the starting dose was given as a full volume of the 1/100dilution (1mg) and thedoseswereplanned to increase graduallyevery 60 minutes by subcutaneous route until a cumulative dose of100 mg was reached. A reaction was noticed 15 minutes afteradministrationof the thirddose (5.5-mg injection,10-mg cumulativedose). Diffuse erythema was noticed on the patient’s face. Phenir-amine maleate was administered and the symptoms successfullydisappeared. Then, the protocol was revised; in this protocol, the 1/100 dilution was administered in 3 doses starting from 0.15 mg andthe doses were gradually increased (0.45 and 0.9 mg; Table 1). Thistime, no reaction occurred and desensitization was completed suc-cessfully. On the second day, 50 mg of anakinrawas administered at1-hour intervals. On the third day, the total dose of 100 mg wasadministered. After desensitization, the intradermal test result wasnegative. During follow-up, the patient took a 15-day treatmentholiday and then was re-desensitized with the same protocol. Shesuccessfully completed the protocol. The patient has continued self-administering anakinra every day, without any problems.