- Email: [email protected]
Drug rash with eosinophilia and systemic signs syndrome in a patient with multiple sclerosis
Clinical Therapeutics/Volume 31, Number 3, 2009
Case Report
Drug Rash With Eosinophilia and Systemic Signs Syndrome in a Patient With Multiple Sclerosis Angelo Caruso, MD1; Rosario Vecchio, MD2; Francesco Patti, MD2; and Sergio Neri, MD1 10 epartment of Internal Medicine) University of Catania) Catania) Italy; and 2First Neurologic Clinic)
University of Catania) Catania) Italy
ABSTRACT Introduction: Drug rash with eosinophilia and systemic signs (DRESS) syndrome is defined by the triad of fever, dermatitis, and internal organ involvement, characteristically occurring with a delay of 3 to 8 weeks after the initiation of treatment with the associated drug. We describe a case of DRESS syndrome in a patient with multiple sclerosis (MS), characterized by a very high eosinophilia and cholestatic hepatitis. Case summary: A 44-year-old white woman with primary progressive MS receiving a multidrug of PO baclofen 75 mg/d, PO piracetam 3 g/d, and IV mitoxantrone 10 mg administered once a month presented to the Multiple Sclerosis Center, University of Catania, Catania, Italy. Eight weeks after the introduction of the latter 2 drugs, the patient had clinical and histological signs of severe cholestatic syndrome followed by hypereosinophilia. All treatments were stopped on admission. Laboratory tests (serologic viral markers, autoantibody pattern antinuclear autoantibodies, antismooth muscle autoantibodies, antimitochondrial autoantibodies, antineutrophil-cytoplasmic autoantibodies, antiliver-kidney-microsomes), abdomen ultrasound, and magnetic resonance cholangiopancreatography did not reveal a cause of the cholestatic syndrome. A liver biopsy was performed because of the persistence of the clinical signs. A Naranjo rating of 4 suggested that mitoxantrone was possibly associated with the occurrence of DRESS. Six months after the first symptoms of DRESS appeared, laboratory tests were normal. Although there are few diagnostic methods for confirming an adverse drug hypersensitivity reaction, a skin prick test suggested a marked positivity for mitoxantrone at all concentrations (100%,50%, 10%). During the first 72 hours, reaction was characterized by skin edema, erythema, and itchiness in the site of inoculation of the drug. The 10580
cal reaction started to regress after 72 hours, with a complete restitution ad integrum in 6 days. A blue discoloration of skin remained for an additional 13 days. Conclusion: We report a case of DRESS syndrome possibly associated with mitoxantrone in a patient with MS. (Clin Ther. 2009;31:580-584) © 2009 Excerpta Medica Inc. Key words: DRESS syndrome, eosinophilia, cholestatic hepatitis, mitoxantrone, multiple sclerosis.
INTRODUCTION The World Health Organization defines an adverse drug reaction (ADR) as a response to a drug that is noxious, unintended, or undesired occurring at doses normally used for the prevention, diagnosis, or treatment of disease. 1 About 80% of all ADRs are type A reactions, defined as predictable and dose-dependent reactions, based on the pharmacology of the drug. In contrast, idiosyncratic drug reactions (type B reactions) cannot be explained on the basis of the pharmacology of the drug, and they do not occur at any dose in most patients. 2 Drug rash with eosinophilia and systemic signs (DRESS) syndrome is a distinct, severe, and potentially fatal drug-hypersensitivity reaction. 3 The syndrome is defined by the combination of fever, dermatitis, and internal organ involvement, generally occurring 3 to 8 weeks after the initiation of treatment. 4 Diagnostic criteria currently employed to characterize this syndrome are hematologic abnormalities (eosinophil >1.5 x 10 9fL or the presence of atypical lymphocytes) or a lymphAccepted for publicationJanuary 20, 2009. doi:l 0.1 016/j.c1 inthera.2009.03.011 0149-2918/$ - see front matter
© 2009 Excerpta Medica Inc. All rights reserved.
Volume 31 Number 3
A. Caruso et al.
adenopathy ::::2 cm in diameter, and the presence of 3 of these criteria establishes the diagnosis. 3 The skin is the organ commonly involved with DRESS syndrome, with a very wide range of manifestation; liver involvement is the most common visceral manifestation. 5 ,6 Lymphadenopathy is frequent, more often generalized and tender. The lymph node histological pattern can be of 2 types, either a benign lymphoid hyperplasia with the preservation of the normal architecture, or a pseudolymphoma aspect. 4 The differential diagnosis of DRESS syndrome can include lymphoma, especially when lymphadenopathy is involved. 7 Nevertheless, some authors suggest that DRESS syndrome and drug-induced pseudolymphoma are 2 distinct entities with different clinical and biologic features and outcomes. s The aromatic anticonvulsivants (phenylhydantoin, phenobarbital, carbamazepine) and sulfonamide are most commonly associated with DRESS syndrome, but a variety of other drugs, especially lamotrigine, allopurinol, calcium channel blockers, neuroleptics, captopril, mood stabilizers, tuberculostatic drugs, antiretroviral drugs, and minocycline have been associated with this clinical entity.4 The factors associated with an increased risk of drug-hypersensitivity reactions include concomitant drug and the presence of a disorder associated with immune dysregulation (eg, autoimmunity diseases).3 We describe a case of DRESS syndrome characterized by very high eosinophilia and cholestatic hepatitis in a patient with multiple sclerosis (MS).
CASE SUMMARY A 44-year-old white woman (weight, 55 kg) with primary progressive MS, diagnosed in 2004, received 2 years of treatment with interferon-B-1a 22 rg (subcutaneous injection 3 times a week) before becoming progressively nonrespondent. Subsequently, because of disease relapse, she initiated combination treatment with baclofen (in January 2006), piracetam, and mitoxantrone (initiated together in September 2007), while discontinuing interferon-B-1a. The dosage regimen was PO baclofen 75 mg/d, PO piracetam 3 g/d, and IV mitoxantrone 10 mg administered once a month. No other drugs were administered by the patient. Eight weeks after the initiation of mitoxantrone and piracetam, the patient presented to the Multiple Sclerosis Center, University of Catania, Catania, Italy, and was admitted because of laboratory tests that March 2009
showed a severe cholestatic syndrome with abnormal liver function (aspartate aminotransferase [AST], 337 lUlL; alanine aminotransferase [ALT], 561 lUlL; (AST and ALT normal upper limit value, 45 IU/L).9 Alkaline phosphatase [ALP], 705 lUlL (normal value, 35-115 lUlL); y-glutamyl transferase [GGT], 447 lUlL (normal value, 3-60 lUlL); and total bilirubin, 19.3 mg/dL (normal value, 0.1-1.2 mg/dL), predominantly indirect. Physical examination showed that she had mild fever (38.5°C), jaundice, and facial edema; no lymphadenopathy was found. The patient reported experiencing symptoms correlated to flu (fever, cough, cold) 1 week prior to admission. All drug treatments were stopped immediately; serologic viral markers for Epstein-Barr virus; cytomegalovirus; herpes virus; hepatitis virus A, B, and C; autoantibody pattern with antinuclear autoantibodies; antismooth muscle autoantibodies; antimitochondrial autoantibodies; antineutrophil-cytoplasmic autoantibodies; and antiliver-kidney-microsomes (anti-LKM)-l and anti-LKM-2 were all within normal limits. Abdomen ultrasound and magnetic resonance cholangiopancreatography were negative as well. After 2 weeks, the patient's total bilirubin level was still high (19.87 mg/dL, almost entirely indirect). A liver biopsy was performed. Histological diagnosis was made on sections stained with hematoxylineosin, Masson's trichromic method, Pearl's Prussian blue, and periodic acid-Schiff stain plus diastase (Figure 1). It showed a normal portal structure, with no signs of piecemeal necrosis. The most prevalent histologic aspect was a canalicular cholestasis characterized by the presence of lakes of bile, organized in bile casts with distended canaliculi. At the third week after admission, cutaneous eruption started across her entire skin surface as macular erythema, which evolved into a red, symmetrical, confluent eruption, that was associated with itchy skin. Laboratory tests showed leukocytosis (15.36 x 10 31 mm 3) with hypereosinophilia (>4000 eosinophils/mL) and liver enzymes increased (AST, 289 lUlL; ALT, 647 lUlL; ALP, 693 lUlL; GGT, 407 lUlL; total bilirubin, 18.1 mg/dL). Steroid therapy with methylprednisolone was initiated at a dose of 20 mg/d for 5 days. During the fifth week, the cholestatic index decreased (total bilirubin, 8.5 mg/dL), and the patient was discharged and followed up weekly in an outpatient setting. 581
Clinical Therapeutics
Figure 1. Liver biopsy found a normal portal structure with a canalicular cholestasis characterized by the presence of lakes of bile, organized in bile casts with distended canaliculi in a 44-year-old patient with multiple sclerosis presenting with drug rash with eosinophilia and systemic signs syndrome.
Six months after experiencing the first symptoms of DRESS syndrome, the patient's laboratory tests were normal. After approval by the institutional review board of the University of Catania, and obtaining informed written consent from the patient, a skin prick test was performed in an attempt to determine the drug most likely associated with the reaction. Based on the pharmacologic medical history, the test was performed with undiluted (100%) and diluted (50%, 10%) drugs. These dilutions, referred to the injection preparation, were performed with physiological saline solution (sodium chloride 0.9%) used as a negative control. In particular, baclofen (pharmaceutical formulation of 10 mg:5 mL) was administered subcutaneously in the following doses: 1 mg/0.5 mL, 0.25 mg/0.5 mL, and 0.01 mg/0.5 mL corresponding, respectively, to the dilutions of 100%,50%, and 10%. Piracetam (3 g/15 mL) was administered subcutaneously in the following doses: 200 mg/0.5 mL (undi-
582
luted), 100 mg/0.5 mL (50% dilution), and 10 mg/ 0.5 mL (10% dilution). Mitoxantrone (2 mg/1 mL) was administered subcutaneously in the following doses: 1 mg/0.5 mL (undiluted), 0.5 mg/0.5 mL (50% dilution), and 0.1 mg/0.5 mL (10% dilution). The result of the skin test was read after 24, 48, and 72 hours (Figure 2). Twenty-four hours after drug inoculation, the skin area corresponding to mitoxantrone reached the maximum reaction, consisting of skin edema, erythema, and itching, without tissue destruction. The local reaction started to regress after 72 hours, with a complete restitution ad integrum in 6 days. A blue discoloration of skin remained for an additional 13 days. Lymphadenopathy was not in the patient's clinical history and was not noted from the time of admission through the end of follow up. A Naranjo score of 4 suggested that mitoxantrone was possibly associated with the occurrence of DRESS syndrome. Volume 31 Number 3
A. Caruso et al.
Figure 2. A skin prick test with (A) baclofen, (B) piracetam, and (C) mitoxantrone using a saline control and concentrations of 100%, 50%, and 10% showed a strong reaction at the site of mitoxantrone inoculation in a 44-year-old patient with multiple sclerosis presenting with drug rash with eosinophilia and systemic signs syndrome.
DISCUSSION Although several drugs can elicit immunological and nonimmunological reactions, diagnostic methods to confirm an adverse drug hypersensitivity reaction are limited. 10 When information on drug allergy is needed for future treatments, the risk of serious reactions cannot be avoided if systemic provocation is carried out,ll with all the risks this involves in patients who, additionally, may evidence a poor general condition or severe involvement of vital organs. Therefore, other methods would be useful, and skin tests with drugs have been used both for screening and diagnosis of adverse drug hypersensitivity reaction. 12 ,13 The assessment of allergic reactions to chemotherapeutic drugs, like mitoxantrone, represents a very significant challenge. Adequate in vivo methods are not available and many of the chemotherapies are irritant or vesicant. Also, in vitro tests are not always easy to manufacture due to the lack of the adequate reagents. 14 The larger clinical experience describes no extravasion reactions with mitoxantrone, suggesting that this agent is a very March 2009
weak vesicant, although the skin site can retain a blue discoloration for several weeks. Thus, mitoxantrone has been classified as an irritant cytostatic. is Because of the irritant characteristics of this cytostatic, when administered subcutaneously, the result cannot be decisive for the diagnosis of drug hypersensitivity reaction. Despite this limitation, we used the skin prick test to investigate the hypersensitivity to drugs that the patient received. The isolated positivity to mitoxantrone in the skin prick test indicated a possible drug hypersensitivity. We utilized this result to modulate the therapeutic regimen of the patient with the hope of minimizing potential ADRs going forward. CONCLUSION We report a case of DRESS syndrome, possibly (Naranjo score, 4) associated with mitoxantrone, with a peculiar clinical presentation characterized by a cholestatic syndrome, rash, and hypereosinophilia (>4000 eosinophils/mL). 583
Clinical Therapeutics
REFERENCES 1. Edwards IR, Aronson JK. Adverse drug reactions: Definitions, diagnosis, and management. Lancet. 2000; 356:1255-1259. 2. Knowles SR, Uerecht J, Shear NH. Idiosyncratic drug reactions: The reactive metabolite syndromes. Lancet. 2000;356:1587-1591. 3. Wolf R, Orion E, Marcos B, Matz H. Life-threatening acute adverse cutaneous drug reactions. Clin Dermatol.2005;23:171-181.
12. Brockow K, Romno A, Blanca M, et al. General considerations for skin test procedures in the diagnosis of drug hypersensitivity. Allergy. 2002; 57:45-51.
14. Davila Gonzalez I, Salazar Saez R, Moreno Rodilla E, et al. Hypersensitivity reactions to chemotherapy drugs. Alergollnmunol Clin. 2000;15: 161-181.
13. Lammintausta K, KortekangasSavolainen O. The usefulness of skin tests to prove drug hypersensitivity. Br J Dermatol. 2005;152:968974.
15. Dorr RT, Alberts DS, Soble M. Lack of experimental vesicant activity for the anticancer agents cisplatin, melphalan, and mitoxantrone. Cancer Chemother Pharmacol. 1986; 16:91-94.
4. Feldman M, Friedman LS, Brandt LJ, Sieisenger M H, eds. Sieisenger & Fordtran's Gastrointestinal and Liver Disease. 8th ed. Philadelphia, Pa: Saunders; 2006:1819.
5. Bocquet H, Bagot M, Roujeau Jc. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS). Semin Cutan Med Surg. 1996; 15:250-257. 6. Wolf R, Matz H, Marcos B, Orion E. Drug rash with eosinophilia and systemic symptoms vs toxic epidermal necrolysis: The dilemma of classification. Clin Dermatol. 2005;23:311-314. 7.
Roujeau Jc. Clinical heterogeneity of drug hypersensitivity. Toxicology.
2005;209:123-129. 8. Callot V, Roujeau JC, Bagot M, et al. Drug-induced pseudolymphoma and hypersensitivity syndrome. Two different clinical entities. Arch Dermatol.1996;132:1315-1321. 9. Dufour DR, LottJA, Nolte FS, et ai,
Diagnosis and monitoring of hepatic injury. I. Performance characteristics of laboratory tests. Clin Chem. 2000;46:2027-2049. 10. Gruchalla R. Understanding drug aliergies.J Allergy Clin Immunol. 2000; 105:5637-5644. 11. Aberer W, Bircher A, Romano A, et ai, for the Euopean Network for Drug Allergy (ENDA) and the EAACI interest group on drug hypersensitivity. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: General considerations. Allergy. 2003;58:854-863.
584
Address correspondence to: Dott. A. Caruso, MD, Department of Internal Medicine, Policlinico of Catania, Via S. Sofia 87, 95123 Catania, Italy. E-mail: [email protected] Volume 31 Number 3
Case Report
Drug Rash With Eosinophilia and Systemic Signs Syndrome in a Patient With Multiple Sclerosis Angelo Caruso, MD1; Rosario Vecchio, MD2; Francesco Patti, MD2; and Sergio Neri, MD1 10 epartment of Internal Medicine) University of Catania) Catania) Italy; and 2First Neurologic Clinic)
University of Catania) Catania) Italy
ABSTRACT Introduction: Drug rash with eosinophilia and systemic signs (DRESS) syndrome is defined by the triad of fever, dermatitis, and internal organ involvement, characteristically occurring with a delay of 3 to 8 weeks after the initiation of treatment with the associated drug. We describe a case of DRESS syndrome in a patient with multiple sclerosis (MS), characterized by a very high eosinophilia and cholestatic hepatitis. Case summary: A 44-year-old white woman with primary progressive MS receiving a multidrug of PO baclofen 75 mg/d, PO piracetam 3 g/d, and IV mitoxantrone 10 mg administered once a month presented to the Multiple Sclerosis Center, University of Catania, Catania, Italy. Eight weeks after the introduction of the latter 2 drugs, the patient had clinical and histological signs of severe cholestatic syndrome followed by hypereosinophilia. All treatments were stopped on admission. Laboratory tests (serologic viral markers, autoantibody pattern antinuclear autoantibodies, antismooth muscle autoantibodies, antimitochondrial autoantibodies, antineutrophil-cytoplasmic autoantibodies, antiliver-kidney-microsomes), abdomen ultrasound, and magnetic resonance cholangiopancreatography did not reveal a cause of the cholestatic syndrome. A liver biopsy was performed because of the persistence of the clinical signs. A Naranjo rating of 4 suggested that mitoxantrone was possibly associated with the occurrence of DRESS. Six months after the first symptoms of DRESS appeared, laboratory tests were normal. Although there are few diagnostic methods for confirming an adverse drug hypersensitivity reaction, a skin prick test suggested a marked positivity for mitoxantrone at all concentrations (100%,50%, 10%). During the first 72 hours, reaction was characterized by skin edema, erythema, and itchiness in the site of inoculation of the drug. The 10580
cal reaction started to regress after 72 hours, with a complete restitution ad integrum in 6 days. A blue discoloration of skin remained for an additional 13 days. Conclusion: We report a case of DRESS syndrome possibly associated with mitoxantrone in a patient with MS. (Clin Ther. 2009;31:580-584) © 2009 Excerpta Medica Inc. Key words: DRESS syndrome, eosinophilia, cholestatic hepatitis, mitoxantrone, multiple sclerosis.
INTRODUCTION The World Health Organization defines an adverse drug reaction (ADR) as a response to a drug that is noxious, unintended, or undesired occurring at doses normally used for the prevention, diagnosis, or treatment of disease. 1 About 80% of all ADRs are type A reactions, defined as predictable and dose-dependent reactions, based on the pharmacology of the drug. In contrast, idiosyncratic drug reactions (type B reactions) cannot be explained on the basis of the pharmacology of the drug, and they do not occur at any dose in most patients. 2 Drug rash with eosinophilia and systemic signs (DRESS) syndrome is a distinct, severe, and potentially fatal drug-hypersensitivity reaction. 3 The syndrome is defined by the combination of fever, dermatitis, and internal organ involvement, generally occurring 3 to 8 weeks after the initiation of treatment. 4 Diagnostic criteria currently employed to characterize this syndrome are hematologic abnormalities (eosinophil >1.5 x 10 9fL or the presence of atypical lymphocytes) or a lymphAccepted for publicationJanuary 20, 2009. doi:l 0.1 016/j.c1 inthera.2009.03.011 0149-2918/$ - see front matter
© 2009 Excerpta Medica Inc. All rights reserved.
Volume 31 Number 3
A. Caruso et al.
adenopathy ::::2 cm in diameter, and the presence of 3 of these criteria establishes the diagnosis. 3 The skin is the organ commonly involved with DRESS syndrome, with a very wide range of manifestation; liver involvement is the most common visceral manifestation. 5 ,6 Lymphadenopathy is frequent, more often generalized and tender. The lymph node histological pattern can be of 2 types, either a benign lymphoid hyperplasia with the preservation of the normal architecture, or a pseudolymphoma aspect. 4 The differential diagnosis of DRESS syndrome can include lymphoma, especially when lymphadenopathy is involved. 7 Nevertheless, some authors suggest that DRESS syndrome and drug-induced pseudolymphoma are 2 distinct entities with different clinical and biologic features and outcomes. s The aromatic anticonvulsivants (phenylhydantoin, phenobarbital, carbamazepine) and sulfonamide are most commonly associated with DRESS syndrome, but a variety of other drugs, especially lamotrigine, allopurinol, calcium channel blockers, neuroleptics, captopril, mood stabilizers, tuberculostatic drugs, antiretroviral drugs, and minocycline have been associated with this clinical entity.4 The factors associated with an increased risk of drug-hypersensitivity reactions include concomitant drug and the presence of a disorder associated with immune dysregulation (eg, autoimmunity diseases).3 We describe a case of DRESS syndrome characterized by very high eosinophilia and cholestatic hepatitis in a patient with multiple sclerosis (MS).
CASE SUMMARY A 44-year-old white woman (weight, 55 kg) with primary progressive MS, diagnosed in 2004, received 2 years of treatment with interferon-B-1a 22 rg (subcutaneous injection 3 times a week) before becoming progressively nonrespondent. Subsequently, because of disease relapse, she initiated combination treatment with baclofen (in January 2006), piracetam, and mitoxantrone (initiated together in September 2007), while discontinuing interferon-B-1a. The dosage regimen was PO baclofen 75 mg/d, PO piracetam 3 g/d, and IV mitoxantrone 10 mg administered once a month. No other drugs were administered by the patient. Eight weeks after the initiation of mitoxantrone and piracetam, the patient presented to the Multiple Sclerosis Center, University of Catania, Catania, Italy, and was admitted because of laboratory tests that March 2009
showed a severe cholestatic syndrome with abnormal liver function (aspartate aminotransferase [AST], 337 lUlL; alanine aminotransferase [ALT], 561 lUlL; (AST and ALT normal upper limit value, 45 IU/L).9 Alkaline phosphatase [ALP], 705 lUlL (normal value, 35-115 lUlL); y-glutamyl transferase [GGT], 447 lUlL (normal value, 3-60 lUlL); and total bilirubin, 19.3 mg/dL (normal value, 0.1-1.2 mg/dL), predominantly indirect. Physical examination showed that she had mild fever (38.5°C), jaundice, and facial edema; no lymphadenopathy was found. The patient reported experiencing symptoms correlated to flu (fever, cough, cold) 1 week prior to admission. All drug treatments were stopped immediately; serologic viral markers for Epstein-Barr virus; cytomegalovirus; herpes virus; hepatitis virus A, B, and C; autoantibody pattern with antinuclear autoantibodies; antismooth muscle autoantibodies; antimitochondrial autoantibodies; antineutrophil-cytoplasmic autoantibodies; and antiliver-kidney-microsomes (anti-LKM)-l and anti-LKM-2 were all within normal limits. Abdomen ultrasound and magnetic resonance cholangiopancreatography were negative as well. After 2 weeks, the patient's total bilirubin level was still high (19.87 mg/dL, almost entirely indirect). A liver biopsy was performed. Histological diagnosis was made on sections stained with hematoxylineosin, Masson's trichromic method, Pearl's Prussian blue, and periodic acid-Schiff stain plus diastase (Figure 1). It showed a normal portal structure, with no signs of piecemeal necrosis. The most prevalent histologic aspect was a canalicular cholestasis characterized by the presence of lakes of bile, organized in bile casts with distended canaliculi. At the third week after admission, cutaneous eruption started across her entire skin surface as macular erythema, which evolved into a red, symmetrical, confluent eruption, that was associated with itchy skin. Laboratory tests showed leukocytosis (15.36 x 10 31 mm 3) with hypereosinophilia (>4000 eosinophils/mL) and liver enzymes increased (AST, 289 lUlL; ALT, 647 lUlL; ALP, 693 lUlL; GGT, 407 lUlL; total bilirubin, 18.1 mg/dL). Steroid therapy with methylprednisolone was initiated at a dose of 20 mg/d for 5 days. During the fifth week, the cholestatic index decreased (total bilirubin, 8.5 mg/dL), and the patient was discharged and followed up weekly in an outpatient setting. 581
Clinical Therapeutics
Figure 1. Liver biopsy found a normal portal structure with a canalicular cholestasis characterized by the presence of lakes of bile, organized in bile casts with distended canaliculi in a 44-year-old patient with multiple sclerosis presenting with drug rash with eosinophilia and systemic signs syndrome.
Six months after experiencing the first symptoms of DRESS syndrome, the patient's laboratory tests were normal. After approval by the institutional review board of the University of Catania, and obtaining informed written consent from the patient, a skin prick test was performed in an attempt to determine the drug most likely associated with the reaction. Based on the pharmacologic medical history, the test was performed with undiluted (100%) and diluted (50%, 10%) drugs. These dilutions, referred to the injection preparation, were performed with physiological saline solution (sodium chloride 0.9%) used as a negative control. In particular, baclofen (pharmaceutical formulation of 10 mg:5 mL) was administered subcutaneously in the following doses: 1 mg/0.5 mL, 0.25 mg/0.5 mL, and 0.01 mg/0.5 mL corresponding, respectively, to the dilutions of 100%,50%, and 10%. Piracetam (3 g/15 mL) was administered subcutaneously in the following doses: 200 mg/0.5 mL (undi-
582
luted), 100 mg/0.5 mL (50% dilution), and 10 mg/ 0.5 mL (10% dilution). Mitoxantrone (2 mg/1 mL) was administered subcutaneously in the following doses: 1 mg/0.5 mL (undiluted), 0.5 mg/0.5 mL (50% dilution), and 0.1 mg/0.5 mL (10% dilution). The result of the skin test was read after 24, 48, and 72 hours (Figure 2). Twenty-four hours after drug inoculation, the skin area corresponding to mitoxantrone reached the maximum reaction, consisting of skin edema, erythema, and itching, without tissue destruction. The local reaction started to regress after 72 hours, with a complete restitution ad integrum in 6 days. A blue discoloration of skin remained for an additional 13 days. Lymphadenopathy was not in the patient's clinical history and was not noted from the time of admission through the end of follow up. A Naranjo score of 4 suggested that mitoxantrone was possibly associated with the occurrence of DRESS syndrome. Volume 31 Number 3
A. Caruso et al.
Figure 2. A skin prick test with (A) baclofen, (B) piracetam, and (C) mitoxantrone using a saline control and concentrations of 100%, 50%, and 10% showed a strong reaction at the site of mitoxantrone inoculation in a 44-year-old patient with multiple sclerosis presenting with drug rash with eosinophilia and systemic signs syndrome.
DISCUSSION Although several drugs can elicit immunological and nonimmunological reactions, diagnostic methods to confirm an adverse drug hypersensitivity reaction are limited. 10 When information on drug allergy is needed for future treatments, the risk of serious reactions cannot be avoided if systemic provocation is carried out,ll with all the risks this involves in patients who, additionally, may evidence a poor general condition or severe involvement of vital organs. Therefore, other methods would be useful, and skin tests with drugs have been used both for screening and diagnosis of adverse drug hypersensitivity reaction. 12 ,13 The assessment of allergic reactions to chemotherapeutic drugs, like mitoxantrone, represents a very significant challenge. Adequate in vivo methods are not available and many of the chemotherapies are irritant or vesicant. Also, in vitro tests are not always easy to manufacture due to the lack of the adequate reagents. 14 The larger clinical experience describes no extravasion reactions with mitoxantrone, suggesting that this agent is a very March 2009
weak vesicant, although the skin site can retain a blue discoloration for several weeks. Thus, mitoxantrone has been classified as an irritant cytostatic. is Because of the irritant characteristics of this cytostatic, when administered subcutaneously, the result cannot be decisive for the diagnosis of drug hypersensitivity reaction. Despite this limitation, we used the skin prick test to investigate the hypersensitivity to drugs that the patient received. The isolated positivity to mitoxantrone in the skin prick test indicated a possible drug hypersensitivity. We utilized this result to modulate the therapeutic regimen of the patient with the hope of minimizing potential ADRs going forward. CONCLUSION We report a case of DRESS syndrome, possibly (Naranjo score, 4) associated with mitoxantrone, with a peculiar clinical presentation characterized by a cholestatic syndrome, rash, and hypereosinophilia (>4000 eosinophils/mL). 583
Clinical Therapeutics
REFERENCES 1. Edwards IR, Aronson JK. Adverse drug reactions: Definitions, diagnosis, and management. Lancet. 2000; 356:1255-1259. 2. Knowles SR, Uerecht J, Shear NH. Idiosyncratic drug reactions: The reactive metabolite syndromes. Lancet. 2000;356:1587-1591. 3. Wolf R, Orion E, Marcos B, Matz H. Life-threatening acute adverse cutaneous drug reactions. Clin Dermatol.2005;23:171-181.
12. Brockow K, Romno A, Blanca M, et al. General considerations for skin test procedures in the diagnosis of drug hypersensitivity. Allergy. 2002; 57:45-51.
14. Davila Gonzalez I, Salazar Saez R, Moreno Rodilla E, et al. Hypersensitivity reactions to chemotherapy drugs. Alergollnmunol Clin. 2000;15: 161-181.
13. Lammintausta K, KortekangasSavolainen O. The usefulness of skin tests to prove drug hypersensitivity. Br J Dermatol. 2005;152:968974.
15. Dorr RT, Alberts DS, Soble M. Lack of experimental vesicant activity for the anticancer agents cisplatin, melphalan, and mitoxantrone. Cancer Chemother Pharmacol. 1986; 16:91-94.
4. Feldman M, Friedman LS, Brandt LJ, Sieisenger M H, eds. Sieisenger & Fordtran's Gastrointestinal and Liver Disease. 8th ed. Philadelphia, Pa: Saunders; 2006:1819.
5. Bocquet H, Bagot M, Roujeau Jc. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS). Semin Cutan Med Surg. 1996; 15:250-257. 6. Wolf R, Matz H, Marcos B, Orion E. Drug rash with eosinophilia and systemic symptoms vs toxic epidermal necrolysis: The dilemma of classification. Clin Dermatol. 2005;23:311-314. 7.
Roujeau Jc. Clinical heterogeneity of drug hypersensitivity. Toxicology.
2005;209:123-129. 8. Callot V, Roujeau JC, Bagot M, et al. Drug-induced pseudolymphoma and hypersensitivity syndrome. Two different clinical entities. Arch Dermatol.1996;132:1315-1321. 9. Dufour DR, LottJA, Nolte FS, et ai,
Diagnosis and monitoring of hepatic injury. I. Performance characteristics of laboratory tests. Clin Chem. 2000;46:2027-2049. 10. Gruchalla R. Understanding drug aliergies.J Allergy Clin Immunol. 2000; 105:5637-5644. 11. Aberer W, Bircher A, Romano A, et ai, for the Euopean Network for Drug Allergy (ENDA) and the EAACI interest group on drug hypersensitivity. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: General considerations. Allergy. 2003;58:854-863.
584
Address correspondence to: Dott. A. Caruso, MD, Department of Internal Medicine, Policlinico of Catania, Via S. Sofia 87, 95123 Catania, Italy. E-mail: [email protected] Volume 31 Number 3