Novel Insights from Clinical Practice

Int Arch Allergy Immunol 2012;157:209212 DOI: 10.1159/000327537

Received: November 16, 2010 Accepted after revision: February 21, 2011 Published online: October 7, 2011

Pyrazinamide-Induced Anaphylaxis: Diagnosed by Skin Test and Successful Desensitization

SevimBavbek nsuYlmaz mrAydn SeilKepilOzdemir
Division of Immunology and Allergy, Department of Chest Diseases, Ankara University School of Medicine, Ankara, Turkey

Established Facts
Pyrazinamide may cause hypersensitivity reactions. Cutaneous manifestations are the most common hypersensitivity reactions to pyrazinamide.

Novel Insights
IgE-mediated anaphylaxis to pyrazinamide is possible. Skin test is helpful in the diagnosis of IgE-mediated anaphylaxis to pyrazinamide.

Key Words Anaphylaxis Pyrazinamide Prick test Desensitization

Introduction

Abstract Pyrazinamide (PZA), an antituberculosis drug, may cause hypersensitivity reactions. Here, we report a case of anaphylaxis secondary to a PZA administration for tuberculosis pleuritis. To the best of our knowledge, this is the first reported case of strongly possible IgE-mediated, PZA-induced anaphylaxis proved by skin prick test and oral provocation/ desensitization. Copyright 2011 S. Karger AG, Basel

Pyrazinamide (PZA) is one of the most effective antituberculous drugs [1, 2] and is generally well tolerated. In addition to causing some common side effects, PZA can also induce hypersensitivity reactions, such as flushing and an instantaneous itchy rash; however, true hypersensitivity reactions are rare [14]. Here, we report a case of anaphylaxis secondary to PZA administration for tuberculosis pleuritis. To the best of our knowledge, this is the first reported case of strongly possible IgE-mediated, PZA-induced anaphylaxis proved by skin prick test and oral provocation/desensitization.
Correspondence to: Prof. Sevim Bavbek Department of Chest Diseases, Division of Immunology and Allergy Ankara University School of Medicine TR06530 Ankara (Turkey) Tel. +90 312 595 6581, E-Mail bavbek@medicine.ankara.edu.tr

2011 S. Karger AG, Basel 10182438/12/15720209$38.00/0 Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Accessible online at: www.karger.com/iaa

Pyrazinamide

Isoniazide

Ethambutol Histamine

Rifampicine

Fig. 1. Skin prick test with antituberculosis drugs.

Case Report
A 44-year-old woman with a recent history of hypersensitivity reaction to antituberculous drugs was admitted to the department of Clinical Immunology and Allergy. According to her history, she had been diagnosed as having tuberculosis pleuritis via pleural biopsy and had been started on a regimen of RIF (Rifcap, 600 mg/day), INH (INH, 300 mg/day), PZA (Pirazinid, 1,500 mg/day) and EMB (Miambutol, 1,500 mg/day; all from Kocak, Turkey). She reported that she had developed diffuse ertyhema and itching, localized particularly on the palmar and plantar regions, as well as shortness of breath, fainting and loss of consciousness within 5 min of the first doses of INH, RIF, PZA and EMB, which had been taken simultaneously. She had been immediately admitted to the emergency department. She reported that her systolic blood pressure had been measured as 50 mm Hg and had been given oxygen treatment and some intravenous medications, the names of which she could not recall. Her symptoms had relieved within 2 h. All drugs were then stopped and the patient was referred to our department. She was hospitalized for evaluation and possible desensitization. The patient had no known allergies or atopic disease. She has never experienced pruritus, dyspnea or fainting, with the exception of the episode following her first dose of medication. She had no other known medical disease, had had no previous treatment with antituberculosis drugs and did not use any other medication. On physical examination, the patient appeared healthy and well nourished with a blood pressure of 110/70 mm Hg, respiratory rate of 22/min, heart rate of 70/ min and arterial oxygen saturation of 96%. Physical examination was normal except for decreased chest sound in the lower part of the left lung on auscultation. While there were changes indicating left-sided pleural effusion in the radiological examination, the other laboratory data were normal. Skin prick tests were performed with PZA tablet, RIF capsule, INH tablet and EMB tablet by the prick to prick method along with a positive control (histamine 0.01%) and a negative control (saline 0.9%) 1 week after the initial reaction. For the prick to prick method, the tablets were smashed in a mortar and diluted with 1 ml of 0.9% NaCI. The RIF capsule was in dry powder form and was also diluted with 1 ml of 0.9% NaCI according to the method previously described [5]. A positive reaction was only seen with PZA, producing a wheal of 3 ! 3 mm surrounded by erythema of 5 mm after 15 min (fig.1).

Table 1. Rapid oral desensitization protocol with PZA

Time min Day 1 0 30 60 90 150 210 270

Dose mg 6.25 12.5 25 50 75 125 250

Cumulative Reactions dose, mg 6.25 18.75 43.75 93.75 168.75 239.75 543.75 500 1,500

Day 2 0 500 30 1,000

generalized ertyhema and pruritus (especially in the palmar and plantar regions), severe headache

Day 3 0 60

750 750

Skin prick tests with PZA were negative in 10 healthy controls. For the negativity on skin test, graded, single blind oral challenge tests were performed with a RIF capsule, an INH tablet and an EMB tablet. The challenge protocol consisted of oral administration of the drugs in increasing doses. On 2 separate days, one fourth and three fourth divided doses of placebo (lactose) were administered at 1-hour intervals. No reaction developed during oral provocation tests and these were accepted as being negative for tested drugs. In terms of the positivity on skin test and negative provocation test results with the 3 previously described antituberculous drugs, PZA was given by modified desensitization protocol based on recent published literature [6], as shown in table1. Informed consent was obtained from the patient before the test. Resuscitation equipment was kept ready at bedside. The first day of desensitization was uneventful, but the patient developed a generalized

210

Int Arch Allergy Immunol 2012;157:209212

Bavbek/Ylmaz/Aydn/Ozdemir

Color version available online

erythema and pruritus (especially on the palmar and plantar regions), along with a severe headache with a 1,500-mg cumulative dose of PZA on the second day. Physical examination was normal with a blood pressure of 110/70 mm Hg. The reactions responded to treatment with pheniramine hydrogen maleate 45.5 mg intramuscular, methylprednisolone 40 mg intravenously, and adrenalin 0.3 mg intramuscular within 30 min. On the next day, a total dose of 1,500 mg PZA was given without incident in two 750-mg divided doses at 1-hour intervals under premedication with 10 mg of cetirizine. The patient is now on quadruple antituberculosis treatment asymptomatically.

Discussion

Hypersensitivity reactions to antituberculosis drugs are seen in 45% of patients who use these drugs, which usually leads to cessation or switching of the therapy. Cutaneous manifestations are the most frequent hypersensitivity reactions to these drugs, and PZA has been implicated in most such cases [7]. Anaphylaxis is also a potential hypersensitivity reaction to this commonly prescribed antituberculosis drug, but it has not been clearly reported before. There is only one report suggesting an anaphylactic-type reaction developed after the initiation of antituberculosis therapy with PZA [8]. In this case, the patient had developed a flush with nausea, dyspnea and abdominal discomfort followed by an itchy rash within minutes of the administration of PZA. However, the case was reported as a case of immediate cutaneous reaction to PZA but was not considered as an anaphylactic reaction, and thus, a skin prick test with PZA was not performed [8]. We performed skin tests with these drugs to evaluate the immunological basis of the reaction as has previously been recommended in the literature [5]. We conducted prick tests with prescribed antituberculosis drugs but did not perform intradermal tests with these drugs since injectable forms of them are not available. Only the prick test with the PZA tablet resulted in a positive test, although it was at the lower limit of positivity. A prick test with PZA was negative in 10 healthy controls, which excluded the possibility of irritation. Due to the urgency of the patients treatment, we had to perform allergologic evaluation earlier than is generally recommended, which is 16 months after the acute event. The short time interval between the severe reaction of the patient and the skin test might have been responsible for the weak positivity of prick test we observed. Additionally, our patient reacted only to PZA among the 4 antituberculosis drugs tested during the oral provocation/desensitization procedure, supporting the causal relationship between the drug and the reaction.
Pyrazinamide-Induced Anaphylaxis

The role of an IgE-mediated mechanism in anaphylaxis is a controversial issue in the instance that a patient has never been exposed to a drug before, with a non-immune mechanism such as prostaglandin or complementmediated mechanism being suggested as possible culprits [9]. Our patient denied previous use of PZA, but she reported that her son had been diagnosed with tuberculosis 1.5 years prior to her diagnosis, and thus, she had been in contact with the same antituberculous drugs through handling them while giving them to her son. On the other hand, more recent data show that previous contact with the causative drug is not an obligatory prerequisite for immune-mediated drug hypersensitivity, and crossreactivity between the involved drug and unrecognized prior exposure to similar chemical structures cannot be ruled out [9, 10] as a cause, as has already been reported in the pholcodine story. IgE antibodies against neuromuscular blocking agents were found to be associated with anaphylaxis and have been attributed to suxamethonium, an ingredient in a commonly used cough syrup, pholcodine [10]. Besides these background data, the possible previous contact, the timing and type of reaction, and the positivity of the prick test strongly suggest an IgE-mediated mechanism to PZA, but in vitro measurement of PZA-specific IgE in the circulation, a limitation in our case, would be complementary. Identification of a culprit drug by skin prick test permits the continuation of the treatment either by removing the culprit drug from treatment or by desensitization [11]. We chose to use desensitization to provide optimum antituberculosis treatment, and rapid oral desensitization was successfully completed using a previously reported desensitization protocol [6]. In conclusion, IgE-mediated anaphylaxis induced by PZA is a possible hypersensitivity reaction to this commonly prescribed antituberculous drug, and this case illustrates both the benefits of performing a skin test in the diagnosis of PZA-induced anaphylaxis and the administration of oral desensitization.

Int Arch Allergy Immunol 2012;157:209212

211

References
1 Aouam K, Chaabane A, Loussaef C, Ben Romdhane F, Boughattas NA, Chakroun M: Adverse effects of antitubercular drugs: epidemiology, mechanisms, and patient management. Med Mal Infect 2007;37:253261. 2 Blumberg HM, Burman WJ, Chaisson RE, et al: American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167:603662. 3 Olivier C, Radal M, Mazaud S, Jonville-Bra AP, Martel C, Autret E: Skin eruption after the first dose of antitubercular quadri-therapy: consideration of pyrazinamide. Arch Pediatr 1998;5:289290. 4 Radal M, Jonville-Bera AP, Van-Egroo C, Carr P, Lemari E, Autret E: Eruption after the 1st dose of standard antitubercular chemotherapy. Thoughts on pyrazinamide. Rev Mal Respir 1998;15:305306. 5 Brockow K, Romano A, Blanca M, Ring J, Picher W, Demoly P: General considerations for skin test procedure in the diagnosis of drug hypersensitivity. Allergy 2002; 57: 45 51. 6 Rodrigues Carvalho S, Silva I, Leiria-Pinto P, Rosado-Pinto J: Rapid oral tolerance induction to isoniazid and pyrazinamide and controlled administration of ethambutol: clinical case. Allergol Immunopathol 2009; 37: 336338. 7 Fekih L, Fenniche S, Boussoffara L, Hassene H, Abdelghaffar H, Belhabib D, Megdiche Mohamed L: Hypersensitivity reactions to antituberculous therapy. Rev Mal Respir 2010;27:673678. 8 Ribi C, Hausher C: Adverse reactions to pyrazinamide. Allergy 2002;57:964965. 9 Schnyder B: Approach to the patient with drug allergy. Immunol Allergy Clin N Am 2009;29:405418. 10 Florvaag E, Johansson SGO: The pholcodine story. Immunol Allergy Clin N Am 2009;29: 419427. 11 Cernadas JR, Brockow K, Romano A, Aberer W, Torres MJ, Bircher A, et al: European Network of Drug Allergy and the EAACI interest group on drug hypersensitivity. General considerations on rapid desensitization for drug hypersensitivity a consensus statement. Allergy 2010;65:13571366.

212

Int Arch Allergy Immunol 2012;157:209212

Bavbek/Ylmaz/Aydn/Ozdemir