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Levamisole-induced thrombosis: Literature review and pertinent laboratory findings
J AM ACAD DERMATOL
e128 Letters
OCTOBER 2011
2. Brandt O, Abeck D, Gianotti R, Burgdorf W. Gianotti-Crosti syndrome. J Am Acad Dermatol 2006;54:136-45. 3. Baldari U, Monti A, Righini M. An epidemic of infantile papular acrodermatitis (Gianotti-Crosti syndrome) due to Epstein-Barr virus. Dermatology 1994;188:203-4. 4. Haug S, Schnopp C, Ring J, F€ olster-Holst R, Abeck D. Gianotti-Crosti syndrome following immunization. Hautarzt 2002;53:683-5. 5. Carmona A, Ome~ naca F, Tejedor J, Merino JM, Vaman T, Dieussaert I, et al. Immunogenicity and safety of AS03adjuvanted 2009 influenza A H1N1 vaccine in children 6-35 months. Vaccine 2010;28:5837-44. doi:10.1016/j.jaad.2011.04.005
Levamisole-induced thrombosis: Literature review and pertinent laboratory findings To the Editor: Levamisole is an immunomodulating agent used as a nonsteroidal therapy for pediatric nephrotic syndrome. Side effects such as retiform purpura and neutropenia have been reported with long-term use. Recently, contamination of the US cocaine supply with levamisole has resulted in hospital admissions for those with cutaneous and immunological findings. We report the case of a man with microvascular thrombosis from suspected levamisole-induced toxicity and present a case series of the literature to identify associated immunological and clinical findings. A 43-year-old man presented with erythema and blister formation occurring over the 2 to 3 days before he came for treatment. Blisters started on bilateral ears and spread to his trunk. He denied pain or pruritus. His medical history was negative. Social history was notable for cocaine usage 3 weeks before presentation. Urine toxicology screen was negative. Physical examination revealed edematous violaceous patches with central hemorrhagic bullae on bilateral ear helices, lobules, and scaphoid fossa (Fig 1, A). Patches of retiform purpura were present on his left shoulder and bilateral flank (Fig 1, B). A biopsy specimen showed microvascular thrombosis (Fig 2). Laboratory workup was notable for white blood cell count 2.6 3 109 /L, absolute neutrophil count of 2.1 3 109 cells/L, elevated sedimentation rate (64 mm/h), C-reactive protein (108 mg/L), partial thromboplastin time (39 seconds), anti-cardiolipin IgM (82 MPL), and lupus partial thromboplastin time (37.2 seconds). Perinuclear anti-neutrophilic cytoplasmic antibody (P-ANCA) was positive ([1:640); protein C (68%), protein S (76%), and antithrombin III (62%) levels were low. Antinuclear antibodies were negative. Levamisole-induced thrombosis was suspected on the basis of clinical and laboratory findings. At 48-hour discharge, skin lesions were stable. One
Fig 1. A, Edematous violaceous patches with central hemorrhagic bullae on right ear helix. B, Retiform purpura present on right lower flank. Suture present at biopsy site.
week later on follow-up, skin lesions were decreased in size and erythema. Levamisole-induced thrombosis and neutropenia is a recently reported condition in cocaine users. An estimated 70% of cocaine is contaminated with levamisole, as it may potentiate the stimulatory effects of cocaine.1,2 Previously, this condition was described in children receiving long-term levamisole treatment for nephrotic syndrome.3 In 2008, large-scale epidemiological studies in New Mexico and Alberta, Canada revealed strong associations between cocaine usage and neutropenia.1,4 We reviewed a series of 13 cases (11 female, 2 male) to determine associated findings. Ages ranged from 18 to 59 years (median 42 years). Ten studies reported absolute neutrophil count less than or equal to 1 3 109 cells/L. Six studies reported positive lupus anticoagulant. Necrotic bullae of the bilateral ears or cheeks appear characteristic of this condition, although propylthiouracil may also cause similar symptoms.5 Other cutaneous findings include purpura and necrotic bullae on the trunk, back, buttock, and lower extremities. The temporal nature between cocaine usage and development of symptoms is unclear; in all cases, symptoms appeared within 4 days of cocaine use. To our knowledge, our case is the only one in which the patient used cocaine longer
J AM ACAD DERMATOL VOLUME 65, NUMBER 4
Letters e129
Fig 2. A, Tissue from abdomen. Nearly all small superficial dermal vessels are occluded by relatively acellular eosinophilic material. B, Tissue from ear. Occlusion of larger vessel by eosinophilic material at level of deep dermis/subcutis. C, Tissue from abdomen. Eosinophilic intravascular material is strongly PAS positive. (A and B, Hematoxylin-eosin stain; C, Periodic acideSchiff stain; original magnifications: A and B, 320; C, 340.)
than 4 days before symptom onset. Levamisole’s short half-life (5.6 hours) makes it difficult to detect in blood serum samples. We present this case report to identify clinical and laboratory indicators of levamisole-induced thrombosis. This condition should be suspected in any patient with similar skin lesions and known illicit drug use. Laboratory studies supporting this diagnosis include low white blood cell count and absolute neutrophil count, presence of P-ANCA or cytoplasmic ANCA (C-ANCA), elevated partial thromboplastin time, negative antinuclear antibodies, and positive lupus anticoagulant. Treatment options include supportive care, oral prednisone, or granulocyte macrophage colony-stimulating factor for neutropenia, although it is unclear how these therapies affect prognosis. In our patient, improvement in lesions was evident without therapy at 1-week follow-up. Repeat laboratory tests were not performed, given clinical improvement. Kachiu C. Lee, MD, MPH,a Keliegh Culpepper, MD,b and Margaret Kessler, MDc Banner Good Samaritan Medical Center, Phoenixa; Dermpath Diagnostics, Tucsonb; and Medical Dermatology Specialists, Phoenixc, Arizona
3. Rongioletti F, Ghio L, Ginevri F, Bleidl D, Rinaldi S, Edefonti A, et al. Purpura of the ears: a distinctive vasculopathy with circulating autoantibodies complicating long-term treatment with levamisole in children. Br J Dermatol 1999;140:948-51. 4. Knowles L, Buxton JA, Skuridina N, Achebe I, Legatt D, Fan S, et al. Levamisole tainted cocaine causing severe neutropenia in Alberta and British Columbia. Harm Reduct J 2009;6:30. 5. Dolman KM, Gans RO, Vervaat TJ, Zevenbergen G, Maingay D, Nikkels RE, et al. Vasculitis and antineutrophil cytoplasmic autoantibodies associated with propylthiouracil therapy. Lancet 1993;342:651-2. doi:10.1016/j.jaad.2011.05.023
A fatal case of cutaneous multicentric epithelioid angiosarcoma To the Editor: Multicentric epithelioid angiosarcoma (EA) involving the small bowel and distal part of the upper extremities has been reported but is rare in the skin.1-3 A 30-year-old woman noted two black painful nodules on her abdomen in May 2002, and soon another 10 lesions developed on her back, forearm, and chest in a month (Fig 1). Initially, blue rubber bleb nevus was suspected. However, the nodules rapidly
Funding sources: None. Conflicts of interest: None declared. Correspondence to: Kachiu C. Lee, MD, MPH, 1111 E. McDowell Rd, Phoenix, AZ 85006 E-mail: [email protected] REFERENCES 1. Agranulocytosis associated with cocaine use e four States, March 2008-November 2009. MMWR Morb Mortal Wkly Rep 2009;58:1381-5. 2. Chang A, Osterloh J, Thomas J. Levamisole: a dangerous new cocaine adulterant. Clin Pharmacol Ther 2010;88:408-11.
Fig 1. Elastic bluish nodule, 1 cm, on erythematous base on back of patient.
e128 Letters
OCTOBER 2011
2. Brandt O, Abeck D, Gianotti R, Burgdorf W. Gianotti-Crosti syndrome. J Am Acad Dermatol 2006;54:136-45. 3. Baldari U, Monti A, Righini M. An epidemic of infantile papular acrodermatitis (Gianotti-Crosti syndrome) due to Epstein-Barr virus. Dermatology 1994;188:203-4. 4. Haug S, Schnopp C, Ring J, F€ olster-Holst R, Abeck D. Gianotti-Crosti syndrome following immunization. Hautarzt 2002;53:683-5. 5. Carmona A, Ome~ naca F, Tejedor J, Merino JM, Vaman T, Dieussaert I, et al. Immunogenicity and safety of AS03adjuvanted 2009 influenza A H1N1 vaccine in children 6-35 months. Vaccine 2010;28:5837-44. doi:10.1016/j.jaad.2011.04.005
Levamisole-induced thrombosis: Literature review and pertinent laboratory findings To the Editor: Levamisole is an immunomodulating agent used as a nonsteroidal therapy for pediatric nephrotic syndrome. Side effects such as retiform purpura and neutropenia have been reported with long-term use. Recently, contamination of the US cocaine supply with levamisole has resulted in hospital admissions for those with cutaneous and immunological findings. We report the case of a man with microvascular thrombosis from suspected levamisole-induced toxicity and present a case series of the literature to identify associated immunological and clinical findings. A 43-year-old man presented with erythema and blister formation occurring over the 2 to 3 days before he came for treatment. Blisters started on bilateral ears and spread to his trunk. He denied pain or pruritus. His medical history was negative. Social history was notable for cocaine usage 3 weeks before presentation. Urine toxicology screen was negative. Physical examination revealed edematous violaceous patches with central hemorrhagic bullae on bilateral ear helices, lobules, and scaphoid fossa (Fig 1, A). Patches of retiform purpura were present on his left shoulder and bilateral flank (Fig 1, B). A biopsy specimen showed microvascular thrombosis (Fig 2). Laboratory workup was notable for white blood cell count 2.6 3 109 /L, absolute neutrophil count of 2.1 3 109 cells/L, elevated sedimentation rate (64 mm/h), C-reactive protein (108 mg/L), partial thromboplastin time (39 seconds), anti-cardiolipin IgM (82 MPL), and lupus partial thromboplastin time (37.2 seconds). Perinuclear anti-neutrophilic cytoplasmic antibody (P-ANCA) was positive ([1:640); protein C (68%), protein S (76%), and antithrombin III (62%) levels were low. Antinuclear antibodies were negative. Levamisole-induced thrombosis was suspected on the basis of clinical and laboratory findings. At 48-hour discharge, skin lesions were stable. One
Fig 1. A, Edematous violaceous patches with central hemorrhagic bullae on right ear helix. B, Retiform purpura present on right lower flank. Suture present at biopsy site.
week later on follow-up, skin lesions were decreased in size and erythema. Levamisole-induced thrombosis and neutropenia is a recently reported condition in cocaine users. An estimated 70% of cocaine is contaminated with levamisole, as it may potentiate the stimulatory effects of cocaine.1,2 Previously, this condition was described in children receiving long-term levamisole treatment for nephrotic syndrome.3 In 2008, large-scale epidemiological studies in New Mexico and Alberta, Canada revealed strong associations between cocaine usage and neutropenia.1,4 We reviewed a series of 13 cases (11 female, 2 male) to determine associated findings. Ages ranged from 18 to 59 years (median 42 years). Ten studies reported absolute neutrophil count less than or equal to 1 3 109 cells/L. Six studies reported positive lupus anticoagulant. Necrotic bullae of the bilateral ears or cheeks appear characteristic of this condition, although propylthiouracil may also cause similar symptoms.5 Other cutaneous findings include purpura and necrotic bullae on the trunk, back, buttock, and lower extremities. The temporal nature between cocaine usage and development of symptoms is unclear; in all cases, symptoms appeared within 4 days of cocaine use. To our knowledge, our case is the only one in which the patient used cocaine longer
J AM ACAD DERMATOL VOLUME 65, NUMBER 4
Letters e129
Fig 2. A, Tissue from abdomen. Nearly all small superficial dermal vessels are occluded by relatively acellular eosinophilic material. B, Tissue from ear. Occlusion of larger vessel by eosinophilic material at level of deep dermis/subcutis. C, Tissue from abdomen. Eosinophilic intravascular material is strongly PAS positive. (A and B, Hematoxylin-eosin stain; C, Periodic acideSchiff stain; original magnifications: A and B, 320; C, 340.)
than 4 days before symptom onset. Levamisole’s short half-life (5.6 hours) makes it difficult to detect in blood serum samples. We present this case report to identify clinical and laboratory indicators of levamisole-induced thrombosis. This condition should be suspected in any patient with similar skin lesions and known illicit drug use. Laboratory studies supporting this diagnosis include low white blood cell count and absolute neutrophil count, presence of P-ANCA or cytoplasmic ANCA (C-ANCA), elevated partial thromboplastin time, negative antinuclear antibodies, and positive lupus anticoagulant. Treatment options include supportive care, oral prednisone, or granulocyte macrophage colony-stimulating factor for neutropenia, although it is unclear how these therapies affect prognosis. In our patient, improvement in lesions was evident without therapy at 1-week follow-up. Repeat laboratory tests were not performed, given clinical improvement. Kachiu C. Lee, MD, MPH,a Keliegh Culpepper, MD,b and Margaret Kessler, MDc Banner Good Samaritan Medical Center, Phoenixa; Dermpath Diagnostics, Tucsonb; and Medical Dermatology Specialists, Phoenixc, Arizona
3. Rongioletti F, Ghio L, Ginevri F, Bleidl D, Rinaldi S, Edefonti A, et al. Purpura of the ears: a distinctive vasculopathy with circulating autoantibodies complicating long-term treatment with levamisole in children. Br J Dermatol 1999;140:948-51. 4. Knowles L, Buxton JA, Skuridina N, Achebe I, Legatt D, Fan S, et al. Levamisole tainted cocaine causing severe neutropenia in Alberta and British Columbia. Harm Reduct J 2009;6:30. 5. Dolman KM, Gans RO, Vervaat TJ, Zevenbergen G, Maingay D, Nikkels RE, et al. Vasculitis and antineutrophil cytoplasmic autoantibodies associated with propylthiouracil therapy. Lancet 1993;342:651-2. doi:10.1016/j.jaad.2011.05.023
A fatal case of cutaneous multicentric epithelioid angiosarcoma To the Editor: Multicentric epithelioid angiosarcoma (EA) involving the small bowel and distal part of the upper extremities has been reported but is rare in the skin.1-3 A 30-year-old woman noted two black painful nodules on her abdomen in May 2002, and soon another 10 lesions developed on her back, forearm, and chest in a month (Fig 1). Initially, blue rubber bleb nevus was suspected. However, the nodules rapidly
Funding sources: None. Conflicts of interest: None declared. Correspondence to: Kachiu C. Lee, MD, MPH, 1111 E. McDowell Rd, Phoenix, AZ 85006 E-mail: [email protected] REFERENCES 1. Agranulocytosis associated with cocaine use e four States, March 2008-November 2009. MMWR Morb Mortal Wkly Rep 2009;58:1381-5. 2. Chang A, Osterloh J, Thomas J. Levamisole: a dangerous new cocaine adulterant. Clin Pharmacol Ther 2010;88:408-11.
Fig 1. Elastic bluish nodule, 1 cm, on erythematous base on back of patient.