Nine episodes of anaphylaxis following cystoscopy caused by Cidex OPA (orthophthalaldehyde)

Transcription

1 Nine episodes of anaphylaxis following cystoscopy caused by Cidex OPA (orthophthalaldehyde) high-level disinfectant in 4 patients after cytoscopy William N. Sokol, MD Newport Beach, Calif Background: Ortho-phthalaldehyde (OPA) is a high-level disinfectant commonly used for processing heat-sensitive medical devices. Objective: We report 4 patients who experienced 9 episodes of anaphylaxis following cystoscopy after a urology practice switched from using Cidex (glutaraldehyde [GTA]) to OPA for disinfecting their cystoscopes. Methods: Allergic evaluations consisted of: skin testing to saline, histamine, glycerin, lidocaine, latex, GTA, and OPA and blood tests for total immunoglobulin E (IgE) and latex specific IgE. Findings: The 4 patients were evaluated after 3 of them had experienced 2 episodes of anaphylaxis and one of them 3 episodes following outpatient cystoscopy for ongoing evaluation of bladder cancer. Skin testing of subjects and controls to lidocaine, latex, latex specific IgE, and GTA was negative. Skin testing to OPA resulted in immediate wheal and flare reactions in all 4 patients within 20 minutes and late reactions at 24 hours but negative reactions in controls. Subsequent to the testing, 3 of the patients returned for repeat cystoscopy in which GTA but not OPA was used to disinfect the cystoscopes and tolerated the procedure. Conclusions: OPA solution should be considered a cause of anaphylactic/allergic reactions following cystoscopy and possibly following instrumentation with other medical devices disinfected by this material. (J Allergy Clin Immunol 2004;114:392-7.) Key words: Anaphylaxis, OPA (ortho-phthalaldehyde), GTA (glutaraldehyde), high-level disinfectant We report 4 patients who experienced 9 episodes of anaphylaxis to a high-level disinfecting agent, orthophthalaldehyde (OPA), which has not been previously reported to cause anaphylactic reactions. In all cases, it was assumed by the treating urologists that the anaphylaxis observed was caused by a known agent (either an antibiotic or local anesthetic) and that agent was avoided in the subsequent procedure. However, despite avoiding the putative cause of the anaphylaxis, the patients were From the University of California Irvine College of Medicine. Received for publication March 15, 2004; revised April 18, 2004; accepted for publication April 19, Disclosure of potential conflict of interest: W. N. Sokol none disclosed. Reprint requests: William N. Sokol, MD, 2011 Westcliff Dr #7, Newport Beach, CA hrinstitute@aol.com /$30.00 Ó 2004 American Academy of Allergy, Asthma and Immunology doi: /j.jaci Abbreviations used GTA: Glutaraldehyde (Cidex) OPA: Ortho-phthalaldehyde (Cidex-OPA) reexposed to OPA and experienced additional anaphylactic episodes. METHODS Latex immunoglobulin E (IgE) testing was performed by the ImmunoCAP method (Pharmacia Diagnostics, Kalamazoo, Mich). Allergen results were expressed in either kilo units per liter (ku/l) or as a percentage of the patient specimen compared to the 0.35 ku/l calibrator (Alternative Scoring Method modified allergen). Total IgE was also measured. Skin testing of latex consisted of cutting a finger off a latex glove and soaking it in saline for 1 hour. The solution was used undiluted as the testing material. Skin testing was performed using 2% lidocaine (Abbott Laboratories, Chicago, Ill) undiluted, for prick testing, and several dilutions of ÿ3, ÿ2,13 10 ÿ1 intradermally, and finally undiluted by subcutaneous injection of 0.5 ml. Positive control consisted of histamine dihydrochloride 10 mg/ml (Hollister-Stier Laboratories LLD, Spokane, Wash). Negative controls were glycerin 50% weight per volume (ALK-Abelló, Wallingford, Ct) and sterile saline (Abbott Laboratories). The glutaraldehyde (GTA) 2.4% (lot #: TPA; expiration: 2/2005) and OPA 0.55% (lot #: TA; expiration: 4/2005) showed final testing strength GTA 24 mg/ml and OPA 5.5 mg/ml. The technique for skin testing involved placing a drop of testing material on the skin and pricking through the drop with a sterile stainless steel prick lanceter ( HGI; Holister-Stier Laboratories, Spokane, Wash). Written informed consent was obtained from all patients. Antigens tested in this fashion were latex, histamine, saline, glycerin, GTA, and OPA on 5 volunteer control subjects and the 4 patients. The results were interpreted at 20 minutes and 24 hours. The wheal and flare reactions, if present, were outlined with a pen and paper tape was placed over the reaction site. The paper tape was then transferred to a blank sheet of paper for measurement. A positive skin test was any hive in the face of a negative (no hive) saline and glycerin control. Description of the cystoscopic procedure Patients with bladder cancer undergo routine observation cystoscopy at periodic intervals for reevaluation of their tumors. The protocol for cystoscopy consisted of utilization of a fiber-optic flexible cystoscope covered by a latex-based sheath. The shaft of the cystoscope was covered with 2% lidocaine. Following the procedure, patients were administered an antibiotic, either Ciprofloxacin (Bayer Corporation, West Haven, Conn) or Macrodantin (Procter and

2 J ALLERGY CLIN IMMUNOL VOLUME 114, NUMBER 2 Sokol 393 Gamble, Cincinatti, Ohio), just before leaving the office. Following the procedure, the cystoscopes were soaked in a disinfectant solution for 12 minutes, then rinsed in sterile water and dried before reuse. The disinfectant used in the practice for the previous 25 years had been GTA. Approximately 2 years prior to the first episode of anaphylaxis, the GTA solution was discontinued. In its place, OPA, a nonvolatile and nonstaining high-level disinfecting product, was substituted. No other change in the disinfectant protocol was made. CASE REPORTS Case 1 C.S., a 70-year-old African American man with a background of urticaria following ingestion of buckwheat, was diagnosed with bladder cancer 2 years before (see Table I). The patient was treated for bladder cancer and underwent in-office cystoscopy on 4 occasions without incident over a period of 1.5 years. Following the fifth procedure, the patient was given his usual tablet of Ciprofloxacin upon leaving the office, but within 30 minutes the patient developed flushing of the skin and generalized itchiness, malaise, and light-headedness followed by generalized urticaria and loss of consciousness. A neighbor called 911, and paramedics treated him with intravenous fluids, oxygen, diphenhydramine, solumedrol, and epinephrine. On the way to the emergency room, the patient regained consciousness. He was stabilized in the hospital and released. The patient reported the reaction to his urologist. It was assumed by the urologist that the problem had been caused by the tablet of Ciprofloxacin, which he had been given as he left the office. Three months later, the patient underwent a subsequent cystoscopy, but just before leaving the office, Macrodantin was given instead of Ciprofloxacin. However, within 15 minutes, he experienced urticaria and itching of the skin, flushing, and dizziness. He immediately drove to the emergency room where he was treated for anaphylaxis and stabilized. Case 2 M.K., a 59-year-old man, was diagnosed with bladder cancer and was treated (see Table I). Thirty minutes after the fifth in-office cystoscopy, the patient developed itching and a rash of the groin, penis, arms, and face, angioedema of the lips, and swelling of the throat. He took 1 tablet of diphenhydramine, which he had on hand, and his symptoms improved. The patient reported this reaction to his urologist and it was assumed that the patient had reacted to Ciprofloxacin given after the procedure. Threemonthslater, thepatientunderwentanothercystoscopy. The procedure was identical except that Macrodantin was given instead of Ciprofloxacin. However, within 15 minutes of the procedure, he felt flushed, itchy, throat swelling, chest tightness, and near syncope. He took 2 tablets of diphenhydramine and drove to the nearest emergency room. He was treated as an anaphylactic reaction over the next 2 to 3 hours and recovered completely. Case 3 G.E., a 78-year-old white man with a history of bladder cancer, was treated with polypectomy (see Table I). He was simultaneously found to have prostate cancer and was treated with 8 weeks of external radiation. The patient underwent 3 uneventful cystoscopies for observation of the bladder cancer and dilatation of a uretheral stricture, which developed postirradiation. Each cystoscopy was followed by a tablet of Ciprofloxacin. On the fourth and fifth cystoscopies he experienced itching and mild donutlike swelling of the penis, but no other systemic symptoms. He did not report these reactions to his urologist. After the sixth cystoscopy and a tablet of Ciprofloxacin, the patient again felt itching and swelling of the penis within 15 minutes of the procedure. However, he also felt abnormal and experienced laryngeal edema and dysphonia followed by urticaria. He drove to the emergency room and was treated as an allergic reaction with epinephrine and diphenhydramine, and he improved. The patient reported the reaction to his urologist who attributed the reaction to lidocaine. The patient returned for a subsequent procedure 3 months later. Lidocaine was not used, only K-Y Jelly (Johnson and Johnson, Arlington, Tex) to lubricate the scope. Following the procedure the patient was given 1 tablet of Ciprofloxacin. Within 20 minutes the patient experienced swelling and itching of the penis, tightness of the throat, urticaria, and laryngeal edema and was taken to the emergency room. He was treated as an allergic reaction and had an uneventful recovery. It was assumed that he had reacted to the Ciprofloxacin. Case 4 B.V., a 67-year-old white man with mild Parkinson s disease and previous myocardial infarction, developed bladder cancer (see Table I). He underwent treatment and 4 observation cystoscopies without adverse reactions. After the fifth cystoscopy in the office, the patient developed swelling and itching of the penis, eyes, tongue, throat, and face and generalized urticaria; he lost consciousness and suffered a grand mal convulsion. The paramedics arrived and the patient was taken immediately to the emergency room, where he was treated as an anaphylactic reaction and recovered uneventfully. The urologist attributed the reaction to the administration of Ciprofloxacin. On the next cystoscopy, approximately 3 months later, the patient was given no antibiotic but otherwise the procedure was identical. However, 15 minutes following the procedure, he developed itching of the penis and swelling of the tongue so that he could not swallow. He had angioedema of the eyelids and face and generalized erythema and itching. The paramedics were again called and he was taken to the emergency room. He was treated as anaphylaxis and recovered. This time it was assumed that the responsible agent was lidocaine. The patient returned for a third cystoscopy 3 months later. Upon this cystoscopy, there were no antibiotics or

3 394 Sokol J ALLERGY CLIN IMMUNOL AUGUST 2004 TABLE I. Manifestations of anaphylactic reactions to OPA Patient Reaction # Time to onset (min) Urticaria Angioedema Penile itching/edema Laryngeal edema LOC/seizure Chest tightness C.S (+) (ÿ) (ÿ) (ÿ) (+) (ÿ) 2 30 (+) (ÿ) (ÿ) (ÿ) (ÿ) (ÿ) M.K (+) (+) (+) (+) (ÿ) (ÿ) 2 30 (+) (+) (+) (+) (ÿ) (+) G.E (+) (+) (+) (+) (ÿ) (ÿ) 2 20 (+) (+) (+) (+) (ÿ) (ÿ) B.V (+) (+) (+) (+) (+) (+) 2 15 (+) (+) (+) (+) (ÿ) (ÿ) 3 30 (+) (+) (+) (+) (+) (ÿ) Total 9/9 7/9 7/9 7/9 3/9 2/9 OPA, Ortho-phthalaldehyde; LOC, loss of consciousness;+, present; ÿ, absent. TABLE II. Allergy testing Patients Radioallergosorbent test to latex IgE (normal, IU) Prick puncture to GTA (24 mg/ml) Prick puncture to OPA (5.5 mg/ml) Controls (N = 5) ND ND Immediate (ÿ) Immediate (ÿ) G.E. <0.35 ku/l (56%) 121 Immediate (ÿ) Immediate 16/50 mm* Late 210 mm** C.S. <0.35 ku/l (81%) 345 Immediate (ÿ) Immediate 14/54 mm* Late 220 mm** B.V. <0.35 ku/l (35%) 27 Immediate (ÿ) Immediate 14/45 mm* Late 250 mm** M.K. <0.35 ku/l (46%) 166 Immediate (ÿ) Immediate 50/80 mm* Late 80 mm** IgE, Immunoglobulin E; GTA, glutaraldehyde (Cidex); OPA, ortho-phthalaldehyde. Prick puncture to histamine was positive and negative to saline, glycerin, latex, and lidocaine in all patients. +, Positive reaction; ÿ, negative reaction. *Wheal/flare in millimeters. **Induration in millimeters. lidocaine used, only K-Y Jelly, and he was given a tablet of 10-mg cetrizine 30 minutes prior to the procedure but no antibiotics. However, approximately 30 minutes following the procedure, the patient again developed penile itching, angioedema of the face and tongue, and urticaria of the skin and he again lost consciousness. The paramedics were called. He was taken to the emergency room and treated as an anaphylactic reaction, and he recovered spontaneously. RESULTS Summary of case reports The anaphylactic reactions were all severe. Of the 9 reactions, 9 had urticaria, 7 had angioedema, 7 had penile itching/edema, 7 had laryngeal edema, 3 experienced loss of consciousness, and one had a convulsion. There was a pattern of asymptomatic sensitization for 4 or 5 cystoscopies followed by anaphylaxis. Penile itching and edema occurred in 7 of the 9 reactions but was a warning symptom before the first anaphylactic reaction in only 1 patient, G.E. Laboratory findings. Informed consent was obtained before any skin test procedures were performed. Skin tests to lidocaine and latex, as well as radioallergosorbent to latex, were performed on all patients and all were negative (see Table II). Total IgE was within normal limits on 3 patients and slightly elevated in one (C.S.). At this time, having discovered no obvious cause for the anaphylactic reactions, we questioned the urologists in detail about every aspect of their cystocopy protocol and discovered that the urology practice had switched from GTA to OPA 2 years before the first reaction. Therefore, by process of elimination, attention was turned to the disinfectant OPA. Skin tests to GTA and OPA were first performed on 5 nonallergic volunteers who served as controls (see Table II). All skin tests to these controls were negative to GTA and OPA. Skin tests to GTA and OPA were then performed on the 4 patients. All 4 patients developed an itchy wheal and flare reaction within 20 minutes to the OPA but not the GTA (see Table II and Fig 1). The 4 patients went on to develop late-phase reactions, which continued to progress for 24 hours. The skin test reactions were quite large. The average wheal, at the 20-minute period of time, was 24.2 mm, and the late phase reaction 24 hours later showed an average induration of 56.3 mm. The delayed reactions were described as swollen, hot,

4 J ALLERGY CLIN IMMUNOL VOLUME 114, NUMBER 2 Sokol 395 FIG 1. Skin test results.

5 396 Sokol J ALLERGY CLIN IMMUNOL AUGUST 2004 tense, and hard and did not exactly mimic the initial early phase reaction but spread beyond the borders of that reaction (see Table II and Fig 1). All patients and controls showed a wheal and flare reaction to histamine and a negative reaction to saline and glycerin. Reexposure of 3 of the patients. Following the finding of the immediate and late-phase hypersensitivity reactions to OPA, the urology practice discontinued the use of this product and switched back to GTA. The protocol for cystoscopy other than the substitution of disinfectant was unchanged. Subsequently, 3 patients (B.V., M.K., and C.S.) returned for outpatient cystoscopy. These patients, who together had previously experienced 7 episodes of anaphylaxis, underwent cystoscopy using GTA as the disinfectant without any untoward reaction. Specifically, there was no swelling or itching of the penis and no manifestations of allergy or anaphylaxis, which had previously been demonstrated when OPA was used as the disinfectant product. DISCUSSION FIG 2. Structure of GTA and OPA. We report 9 episodes of anaphylaxis in 4 patients caused by the high-level disinfectant OPA. The evidence supporting that OPA was the cause of these reactions includes a compatible history, the absence of other known causes (ie, latex, lidocaine, or drug allergy), and the finding of immediate and late-phase skin reactions to OPA solution in each of the patients and negative reactions on skin testing to the 5 controls. Further proof of the cause of the reactions was obtained by demonstrating negative skin testing to GTA in the 4 patients and uneventful subsequent cystoscopy using GTA as a disinfecting product in 3 of the 4 patients. OPA, which contains 0.55% ortho-phthalaldehyde, is an organic aromatic compound that received clearance from the Food and Drug Administration in October 1999 to be used as a high-level chemical disinfectant. Cidex- OPA is recommended for reprocessing of heat-sensitive medical devices, such as endoscopy equipment and transesophageal echo probes, as an alternative to Cidex GTA. Both of these agents are recognized as high-level disinfectants. However, despite the similarity of the 2 products implied in the name, these 2 molecules are significantly different both chemically and biochemically (Fig 2). OPA, the active ingredient of the disinfectant, is a member of the aldehyde family, as is GTA. Aldehydes are widely used for the manufacture of synthetic resins and for making dyestuff, flavorings, perfumes, and as disinfectants. Although allergic reactions to GTA are well known 1-5 and an IgE mechanism has been proposed, 6 no previous reports of allergic reactions to OPA exist in the medical literature. There is 1 report of chemical burn injury secondary to intraopertive transesophageal echocardiography 7 but no allergic reactions. The package insert does state that exacerbations of asthma and bronchitis have been reported. After finding the cause of these reactions we contacted the manufacturer and were informed that they have received incident reports on 9 patients of allergic reactions to OPA, all from urology practices (personal communication: Joseph M. Ascenzi, PhD, Advanced Sterilization Products, a Johnson & Johnson company). The repeated exposure of the patients to OPA residues on the scopes first sensitized them over the initial 4 or 5 procedures and upon reexposure produced anaphylaxis. Because OPA is much less water soluble than GTA (personal communication: Joseph M. Ascenzi, PhD, Advanced Sterilization Products, a Johnson & Johnson company), it is possible that the established protocol for rinsing the disinfectants off the cystoscopes used by the urologists was sufficient to remove sensitizing doses of the water-soluble GTA but not of the less water-soluble OPA. On the other hand, water solubility may not be a determining factor, and OPA may simply be much more allergenic than GTA. The immediate and late-phase skin testing reactions that we observed strongly suggest an IgEmediated mechanism for these reactions. However, the demonstration of allergy specific IgE will be required to confirm this impression. In view of the large reactions on skin testing in the 4 patients, it is recommended that lower concentrations of OPA be used for any further skin testing (ie, 0.55 mg/ml or mg/ml). At this time, these reactions appear to be restricted to urology. However, other specialties that use OPA as a disinfectant for their devices may also be experiencing allergic reactions (ie, pulmonology, gastroenterology, otolaryngology, or cardiology). Further investigation of this phenomenon is warranted as this product is being widely used and may even help to explain some of the adverse event reports in a variety of fields associated with

6 J ALLERGY CLIN IMMUNOL VOLUME 114, NUMBER 2 Sokol 397 endoscope use. Until further investigation is performed, the use of OPA as a disinfectant for cystoscopy in urology practices should be discontinued. REFERENCES 1. DeStefano F, Sirirutta S, Turk A, McCoach JS, Burge PS, Monaldi J. Occupational asthma due to glutaraldehyde. Arch Chest Dis 1999;53: Gannon PF, Bright P, Campbell M, O Hickey SP, Sherwood Burge P. Occupational asthma due to glutaraldehyde and gormaldehyde in endoscopy and x-ray departments. Thorax 1995;50: Corrado OJ, Osman J, Davies RJ. Asthma and rhinitis after exposure to glutaraldehyde in endoscopy units. Hum Toxicol 1986;5: Patczynski C, Walusiak J, Ruta U, Gorski P. Occupational asthma and rhinitis due to glutaraldehyde; changes in nasal lavage fluid after specific inhalatory challenge tests. Allergy 2001;56: Nettis E, Colanardi M, Soccio A, Ferrannini A, Tursi A. Occupational irritant and allergic contact dermatitis among healthcare workers. Contact Dermatitis 2002;46: Curran AD, Burge PS, Wiley K. Clinical and immunological evaluation of workers exposed to glutaraldehyde. Allergy 1996;51: Venticnque SG, Kashyap VS, O Connell RJ. Chemical burn injury secondary to intraopertive transesophageal echocardiography. Anesth Analg 2003;97: