http://informahealthcare.com/cot ISSN: 1556-9527 (print), 1556-9535 (electronic) Cutan Ocul Toxicol, Early Online: 1–3 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/15569527.2014.961071
CASE REPORT
Acute generalized exanthematous pustulosis induced by iodixanol (Visipaque): a serious reaction to a commonly used drug
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 02/14/15 For personal use only.
Unal Ozturk1, Mustafa Azmi Sungur1, Tugba Karakas2, Kamil Mulayim2, and Perihan Ozturk2 1
Department of Cardiology, Kahramanmaras Necip Fazil Sehir Hospital, Kahramanmaras, Turkey and 2Department of Dermatology, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey Abstract
Keywords
Acute generalized exanthematous pustulosis (AGEP) is an acute sterile pustular eruption most commonly induced by medications. Although antibiotics are the most commonly accused drugs in AGEP, non-antibiotic agents may also cause this disease. We present a case of AGEP following use of iodixanol for coronary angiography in a 61-year-old woman. Given the wide use of this substance in cardiology, clinicians should be aware of this potential complication.
Case, generalized, iodixanol, pustulosis
Introduction Acute generalized exanthematous pustulosis (AGEP) is a rare cutaneous rash characterized by the abrupt onset of a widespread pustular rash often accompanied by fever1. AGEP is most commonly caused by medications and but rarely can be associated with viral (e.g. enterovirus) infections, exposure to inorganic compounds (e.g. mercury) or contrast agents2. Iodixanol (VisipaqueÕ ) is a water-soluble, low-osmolar, non-ionic, dimeric, hexa-iodinated contrast medium (CM) used for coronary angiography and percutaneous coronary interventions (PCI)3. Non-ionic CM is known to decrease the incidence of allergic adverse reactions when compared to ionic CM. Adverse reaction to CM can be divided into immediate and late. Late reactions occur in between 0.5 and 2% of patients exposed to non-ionic, iodinated X-ray CM4. Late-onset allergy-like reactions after exposure become apparent from 1 h to 7 days3. As far as we know, iodixanol-induced AGEP has not been previously reported in the English literature. We experienced a rare case of AGEP associated with the use of non-ionic CM during PCI.
Case A 61-year-old female patient was admitted to the hospital with the complaint of stable angina pectoris. Elective coronary angiography was performed using iodixanol as CM.
Address for correspondence: Dr Perihan Ozturk, E-mail: drperihanozturk @hotmail.com
History Received 7 July 2014 Revised 31 July 2014 Accepted 29 August 2014 Published online 30 October 2014
Obstructive right coronary artery lesion was detected, and bare metal stent was implanted in the same session. One day after the procedure, a generalized pustular eruption and fever (38.5 C) began in an otherwise healthy patient. Physical examination revealed hundreds of small, non-follicular pustules over an erythematous–edematous skin, which started to scale in flexural areas. The mucous membranes were unaffected and Nikolsky sign was negative on both effected and healthy skin (Figure 1). She denied having a personal or family history of skin disease, including psoriasis. Other systemic examinations were normal. She was not taking any medication except clopidogrel, discontinuation of which was not possible due to recent stent implantation. Significant neutrophilic leukocytosis was observed in the blood count (14 103 leukocytes with 86% neutrophils). Eryhthrocyte sedimentation rate was normal and other laboratory parameters were unremarkable. Gram stain of the pustular contents showed only scattered neutrophils and eosinophils. The culture was sterile. Punch biopsy specimen is taken from one of the lesions. There are irregularly acantosis, microscopic abse focus (including neutrophil leukocyte) in epidermis. Also, there are inflammatory cell infiltration (including pericapillary eosinophil leukocyte) in upper dermis (Figure 2). Biopsy findings supported our clinical suspicion of AGEP as our patient fulfilled four out of the five classic criteria proposed by Roujeau et al.5 (acute pustular eruption, fever 438 C, neutrophilia (with or without eosinophilia) and subcorneal or intraepidermal pustules on biopsy). The patient was treated with intravenous methylprednisolon (32 mg/day) together with local moisturizers and topical steroids. The appearance of new pustules stopped
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 02/14/15 For personal use only.
2
U. Ozturk et al.
Cutan Ocul Toxicol, Early Online: 1–3
Figure 2. There are irregularly acantosis, microscopic abse focus in epidermis and inflammatory cell infiltration in upper dermis.
Figure 1. There are non-follicular erythematous–edematous skin.
pustules
over
an
in 3 days, and the healing pursued with exfoliation. After 3 days, the drug was tapered gradually within 10 days and then stopped. Patient was discharged on the 10th day with no apparent skin lesions. One month later, she presented to emergency department with acute coronary syndrome. Coronary angiography and PCI for stent thrombosis was performed with Iodixanol (VisipaqueÕ ) again. Her eruptions and fever began after 48 h of exposure. She was treated in the same manner as before and recovered with desquamation in a week.
Discussion AGEP was first described in 1980 by Beylot et al. as an acute pustular reaction pattern distinct from pustular psoriasis6. It is a rare but severe cutaneous adverse reaction that generally presents with an acute edematous erythema and small non-follicular sterile pustules mostly beginning in folds or face and becomes diffuse within hours1. Characteristic features include numerous non-follicular, subcorneal, sterile pustules overlying erythema, fever (38 C) and neutrophilic leukocytosis6. A mild eosinophilia may be present in about one-third of the patients. Our patient had fever, neutrophilic leukocytosis and characteristic sterile pustules in both attacks. The vast majority of cases are caused by drugs (90%). Among medications, antibiotics, including b-lactams and macrolides, are the most common triggers of this disease. There is also a strong association with terbinafine, diltiazem and hydroxychloroquine. New medications are steadily being reported to cause AGEP as awareness of this cutaneous drug reaction increases7. This case, to our knowledge, is the first report relating iodixanol to AGEP.
AGEP is one of the most recognizable drug reaction patterns. Once the diagnosis is established, disclosure of the causative agent is desirable which often remains unclear. In our case, the patient tested herself with the second coronary intervention and eliminated the need for drug provocation test. A skin biopsy may show (spongiform or non-spongiform) subcorneal or intradermal pustules, or both, oedema of the papillary dermis, perivascular infiltrates with neutrophils and exocytosis of some eosinophils and focal necrotic keratinocytes. The typical changes of psoriasis such as acanthosis and papillomatosis are usually absent7. In our patient, histopathologic changes were consistent with AGEP. Symptoms and signs resolve following discontinuation of the offending agent6. Our patient recovered uneventful in 10 days. AGEP is a rare and potentially serious adverse cutaneous reaction that occurs in response to many medications. Based on our case report, iodixanol can now be added to the list of potential triggers. Given the wide use of this substance in cardiology, clinicians should be aware of this potential complication.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References 1. Fernando SL. Acute generalised exanthematous pustulosis. Australas J Dermatol 2012;53:87–92. 2. Sadeghpour M, Bunick CG, Robinson DM, et al. Midodrineinduced acute generalized exanthematous pustulosis. Cutis 2014; 93:E17–E20. 3. Choi CU, Rha SW, Suh SY, et al. Extensive exfoliative dermatitis induced by non-ionic contrast medium iodixanol (Visipaque) used during percutaneous coronary intervention. Int J Cardiol 2008; 124:e25–e27.
DOI: 10.3109/15569527.2014.961071
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 02/14/15 For personal use only.
4. Sa´nchez-Pe´rez J, F-Villalta MG, Ruı´z SA, Garcı´a Diez A. Delayed hypersensitivity reaction to the non-ionic X-ray contrast medium Visipaque (iodixanol). Contact Dermatitis 2003;48:167. 5. Roujeau JC, Bioulac-Sage P, Bouseau C. Acute generalized exanthematous pustulosis: analisis of 63 cases. Arch Dermatol 1991;127:1333–1338.
Generalized pustulosis induced by iodixanol
3
6. Ellerbroek JC, Cleveland MG. Clopidogrel-associated acute generalized exanthematous pustulosis. Cutis 2011;87: 181–185. 7. Sidoroff A, Halevy S, Bavinck JN, et al. Acute generalized exanthematous pustulosis (AGEP) – a clinical reaction pattern. J Cutan Pathol 2001;28:113–119.
CASE REPORT
Acute generalized exanthematous pustulosis induced by iodixanol (Visipaque): a serious reaction to a commonly used drug
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 02/14/15 For personal use only.
Unal Ozturk1, Mustafa Azmi Sungur1, Tugba Karakas2, Kamil Mulayim2, and Perihan Ozturk2 1
Department of Cardiology, Kahramanmaras Necip Fazil Sehir Hospital, Kahramanmaras, Turkey and 2Department of Dermatology, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey Abstract
Keywords
Acute generalized exanthematous pustulosis (AGEP) is an acute sterile pustular eruption most commonly induced by medications. Although antibiotics are the most commonly accused drugs in AGEP, non-antibiotic agents may also cause this disease. We present a case of AGEP following use of iodixanol for coronary angiography in a 61-year-old woman. Given the wide use of this substance in cardiology, clinicians should be aware of this potential complication.
Case, generalized, iodixanol, pustulosis
Introduction Acute generalized exanthematous pustulosis (AGEP) is a rare cutaneous rash characterized by the abrupt onset of a widespread pustular rash often accompanied by fever1. AGEP is most commonly caused by medications and but rarely can be associated with viral (e.g. enterovirus) infections, exposure to inorganic compounds (e.g. mercury) or contrast agents2. Iodixanol (VisipaqueÕ ) is a water-soluble, low-osmolar, non-ionic, dimeric, hexa-iodinated contrast medium (CM) used for coronary angiography and percutaneous coronary interventions (PCI)3. Non-ionic CM is known to decrease the incidence of allergic adverse reactions when compared to ionic CM. Adverse reaction to CM can be divided into immediate and late. Late reactions occur in between 0.5 and 2% of patients exposed to non-ionic, iodinated X-ray CM4. Late-onset allergy-like reactions after exposure become apparent from 1 h to 7 days3. As far as we know, iodixanol-induced AGEP has not been previously reported in the English literature. We experienced a rare case of AGEP associated with the use of non-ionic CM during PCI.
Case A 61-year-old female patient was admitted to the hospital with the complaint of stable angina pectoris. Elective coronary angiography was performed using iodixanol as CM.
Address for correspondence: Dr Perihan Ozturk, E-mail: drperihanozturk @hotmail.com
History Received 7 July 2014 Revised 31 July 2014 Accepted 29 August 2014 Published online 30 October 2014
Obstructive right coronary artery lesion was detected, and bare metal stent was implanted in the same session. One day after the procedure, a generalized pustular eruption and fever (38.5 C) began in an otherwise healthy patient. Physical examination revealed hundreds of small, non-follicular pustules over an erythematous–edematous skin, which started to scale in flexural areas. The mucous membranes were unaffected and Nikolsky sign was negative on both effected and healthy skin (Figure 1). She denied having a personal or family history of skin disease, including psoriasis. Other systemic examinations were normal. She was not taking any medication except clopidogrel, discontinuation of which was not possible due to recent stent implantation. Significant neutrophilic leukocytosis was observed in the blood count (14 103 leukocytes with 86% neutrophils). Eryhthrocyte sedimentation rate was normal and other laboratory parameters were unremarkable. Gram stain of the pustular contents showed only scattered neutrophils and eosinophils. The culture was sterile. Punch biopsy specimen is taken from one of the lesions. There are irregularly acantosis, microscopic abse focus (including neutrophil leukocyte) in epidermis. Also, there are inflammatory cell infiltration (including pericapillary eosinophil leukocyte) in upper dermis (Figure 2). Biopsy findings supported our clinical suspicion of AGEP as our patient fulfilled four out of the five classic criteria proposed by Roujeau et al.5 (acute pustular eruption, fever 438 C, neutrophilia (with or without eosinophilia) and subcorneal or intraepidermal pustules on biopsy). The patient was treated with intravenous methylprednisolon (32 mg/day) together with local moisturizers and topical steroids. The appearance of new pustules stopped
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 02/14/15 For personal use only.
2
U. Ozturk et al.
Cutan Ocul Toxicol, Early Online: 1–3
Figure 2. There are irregularly acantosis, microscopic abse focus in epidermis and inflammatory cell infiltration in upper dermis.
Figure 1. There are non-follicular erythematous–edematous skin.
pustules
over
an
in 3 days, and the healing pursued with exfoliation. After 3 days, the drug was tapered gradually within 10 days and then stopped. Patient was discharged on the 10th day with no apparent skin lesions. One month later, she presented to emergency department with acute coronary syndrome. Coronary angiography and PCI for stent thrombosis was performed with Iodixanol (VisipaqueÕ ) again. Her eruptions and fever began after 48 h of exposure. She was treated in the same manner as before and recovered with desquamation in a week.
Discussion AGEP was first described in 1980 by Beylot et al. as an acute pustular reaction pattern distinct from pustular psoriasis6. It is a rare but severe cutaneous adverse reaction that generally presents with an acute edematous erythema and small non-follicular sterile pustules mostly beginning in folds or face and becomes diffuse within hours1. Characteristic features include numerous non-follicular, subcorneal, sterile pustules overlying erythema, fever (38 C) and neutrophilic leukocytosis6. A mild eosinophilia may be present in about one-third of the patients. Our patient had fever, neutrophilic leukocytosis and characteristic sterile pustules in both attacks. The vast majority of cases are caused by drugs (90%). Among medications, antibiotics, including b-lactams and macrolides, are the most common triggers of this disease. There is also a strong association with terbinafine, diltiazem and hydroxychloroquine. New medications are steadily being reported to cause AGEP as awareness of this cutaneous drug reaction increases7. This case, to our knowledge, is the first report relating iodixanol to AGEP.
AGEP is one of the most recognizable drug reaction patterns. Once the diagnosis is established, disclosure of the causative agent is desirable which often remains unclear. In our case, the patient tested herself with the second coronary intervention and eliminated the need for drug provocation test. A skin biopsy may show (spongiform or non-spongiform) subcorneal or intradermal pustules, or both, oedema of the papillary dermis, perivascular infiltrates with neutrophils and exocytosis of some eosinophils and focal necrotic keratinocytes. The typical changes of psoriasis such as acanthosis and papillomatosis are usually absent7. In our patient, histopathologic changes were consistent with AGEP. Symptoms and signs resolve following discontinuation of the offending agent6. Our patient recovered uneventful in 10 days. AGEP is a rare and potentially serious adverse cutaneous reaction that occurs in response to many medications. Based on our case report, iodixanol can now be added to the list of potential triggers. Given the wide use of this substance in cardiology, clinicians should be aware of this potential complication.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References 1. Fernando SL. Acute generalised exanthematous pustulosis. Australas J Dermatol 2012;53:87–92. 2. Sadeghpour M, Bunick CG, Robinson DM, et al. Midodrineinduced acute generalized exanthematous pustulosis. Cutis 2014; 93:E17–E20. 3. Choi CU, Rha SW, Suh SY, et al. Extensive exfoliative dermatitis induced by non-ionic contrast medium iodixanol (Visipaque) used during percutaneous coronary intervention. Int J Cardiol 2008; 124:e25–e27.
DOI: 10.3109/15569527.2014.961071
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 02/14/15 For personal use only.
4. Sa´nchez-Pe´rez J, F-Villalta MG, Ruı´z SA, Garcı´a Diez A. Delayed hypersensitivity reaction to the non-ionic X-ray contrast medium Visipaque (iodixanol). Contact Dermatitis 2003;48:167. 5. Roujeau JC, Bioulac-Sage P, Bouseau C. Acute generalized exanthematous pustulosis: analisis of 63 cases. Arch Dermatol 1991;127:1333–1338.
Generalized pustulosis induced by iodixanol
3
6. Ellerbroek JC, Cleveland MG. Clopidogrel-associated acute generalized exanthematous pustulosis. Cutis 2011;87: 181–185. 7. Sidoroff A, Halevy S, Bavinck JN, et al. Acute generalized exanthematous pustulosis (AGEP) – a clinical reaction pattern. J Cutan Pathol 2001;28:113–119.
