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Purpuric skin eruption in an illicit drug user: Levamisole-induced vasculitis
American Journal of Emergency Medicine xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Case Report
Purpuric skin eruption in an illicit drug user Abstract A 36-year-old woman presented to the emergency department with 5 days of worsening painful bruising that started on her legs and spread to her torso and face. She reported recent use of heroin and cocaine. On examination, she was tachycardic with a nonblanching, painful, purpuric skin eruption on bilateral thighs, chest, upper arms, right cheek, and ears. Focal areas of necrosis without crepitance were noted. Emergency department workup ensued for possible drug-induced or bacterial coagulopathy with concern for purpura fulminans, disseminated intravascular coagulation, and/or necrotizing fasciitis. Empiric antibiotics were started, and patient was admitted to the progressive care unit where further workup confirmed levamisole-induced vasculitis. Levamisoleinduced vasculitis is an immune complex–mediated cutaneous small vasculitis syndrome associated with cocaine adulterated with levamisole. A characteristic palpable, painful, purpuric retiform rash with or without central necrosis is accompanied by typical laboratory findings of leukopenia, neutropenia, and positive autoantibodies[1,2]. Histologic features include microvascular fibrin thrombi and leukocytoclastic vasculitis of small vessels [1]. Treatment goals are preventing skin infection with broad-spectrum antibiotics and, if necessary, transfer to a burn center for definitive management of lesions. A 36-year-old white woman presented to the emergency department (ED) with 5 days of gradually worsening painful bruising that started on her legs and spread to her torso and face. She reported no trauma, recent illness, or fevers. Her history is pertinent for leukopenia, previous methicillin-resistant Staphylococcus aureus and hepatitis C virus infections, and intravenous heroin and crack cocaine use. She reported to the emergency physician last use of heroin 3 days ago and last smoking of cocaine 5 days ago. She was found to have sinus tachycardia at 128 beats per minute without murmur, blood pressure of 168/97, respiratory rate of 20 breaths per minute, and an oral temperature of 37.3°C. A nonblanching, painful, purpuric skin eruption was noted on bilateral thighs, chest, upper arms, right cheek and ears (Figs. 1 and 2). Focal areas of necrosis without crepitance were noted. Distal pulses were found to be equal and palpable in all extremities. She had benign chest and abdominal examinations. She had no measurable neurologic deficits. Emergency department workup ensued for possible drug-induced or bacterial coagulopathy with concern for purpura fulminans, disseminated intravascular coagulation (DIC), and/or necrotizing fasciitis. This resulted in evidence of elevated erythrocyte sedimentation rate, C-reactive protein, protime prolonged partial thromboplastin, Ddimer, and a microcytic anemia. Leukocytes and platelets were within normal limits. She had positive urine cocaine metabolites, methadone, opiates, and cannabinoids. Empiric treatment included high-
dose intravenous clindamycin and piperacillin/tazobactam and 2 L of 0.9% sodium chloride. Fentanyl 50 μg was provided for analgesia. Consultation was made to general surgery, and the patient was admitted to the hospitalist medical team for purpuric rash and coagulopathy without DIC. Purpuric skin lesions presenting to the ED raise concern for lifethreatening infections (meningococcemia, necrotizing fasciitis, and septic emboli), coagulopathies (DIC), and autoimmune disorders (vasculitis and Henoch-Schonlein purpura). Our patient was afebrile, and the history of recent intravenous drug use and cocaine use with distribution of the purpuric eruption raised suspicion for levamisole-induced vasculitis. However, infectious etiology should not be ruled out based on initial presentation and ED workup alone. Patients should be admitted on empiric antibiotics after appropriate hemodynamic stabilization for further diagnostics and treatment. Levamisole is a veterinary anthelminthic drug that has become an increasingly common additive to cocaine over the past decade. Levamisole was used as an immunomodulatory drug to treat colorectal cancer and various dermatologic pathologies before being withdrawn from the market in the United States in 1999 secondary to side effects including agranulocytosis. In 2013, the Drug Enforcement Administration reported that up to 70% of illicit cocaine samples in the United States contain levamisole [1]. It is proposed that levamisole is used as an additive secondary to its agonist activity at nicotinic receptors, potentiating the effects of cocaine [2]. The presence of levamisole can be tested in both plasma and urine, although results may be negative depending on last drug use as its plasma elimination half-life of 5 to 6 hours [3]. Levamisole-induced vasculitis is an immune complex–mediated cutaneous small vasculitis syndrome associated with cocaine adulterated with levamisole. The characteristic skin findings are a palpable, painful, purpuric retiform rash with or without central necrosis [4]. It is associated often with pharmaceuticals—penecillins, cephalosporins, sufonamides, phenytoin, and allopurinol—as well as with hepatitis B and C viruses, HIV, and chronic bacterial infections [5]. Skin manifestations occur on average 7 to 10 days after drug exposure and are predicated to the cheeks, nose, ears, trunk, and extremities [6]. Depending on the degree of necrosis, the lesions may result in surgical debridement, skin grafting and/or amputation [6]. Histologic features include microvascular fibrin thrombi and leukocytoclastic vasculitis of small vessels [4]. Typical laboratory findings include leukopenia, neutropenia, and positive autoantibodies including perineuclear and cytoplasmic Anti-Neutrophil Cytoplasmic Antibodies, antinuclear antibody, and lupus anticoagulant. [7] There is currently no standard treatment for levamisole-induced vasculitis. Treatment begins with stopping the inciting agent. As patients are often neutropenic, it is important to prevent infection of
0735-6757/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Graff N, et al, Purpuric skin eruption in an illicit drug user, Am J Emerg Med (2015), http://dx.doi.org/10.1016/ j.ajem.2015.11.055
2
N. Graff et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
Fig. 1. Painful purpura of the right ear with necrosis.
skin lesions with broad-spectrum antibiotic coverage. Depending on the extent of skin involvement and necrosis, patients may require transfer to a burn unit for definitive management of lesions. Our patient remained hemodynamically stable without evidence of DIC but continued to demonstrate a coagulopathy and developed leukopenia (3800/μL). No evidence of bacteremia, endocarditis, active hepatitis C virus, or antiphospholipid antibodies were identified. As suspected, levamisole was determined to be present in the patient's urine. Punch biopsied tissue revealed superficial and deep small vascular wall necrosis with neutrophilic infiltrate and luminal fibrin thrombi. This is compatible with levamisole-induced vasculitis likely from cocaine and/or heroin use, despite negative rheumatologic workup. The patient was transferred to a university hospital burn unit for symptomatic treatment due to diffuse skin loss over her lower extremities. She is back home and doing well with planned skin grafting once healed.
Nicholas Graff DO Kristen Whitworth DO ⁎ Christopher Trigger MD Lakeland Health Emergency Medicine Residency Program Lakeland Health, Saint Joseph, MI 49085 ⁎ Corresponding author. 2103 Langley Avenue, Saint Joseph, MI 49085 E-mail addressess: [email protected] [email protected] http://dx.doi.org/10.1016/j.ajem.2015.11.055
Fig. 2. Nonblanching, painful purpura on bilateral legs with hemorrhagic bullae and necrosis.
References [1] Mallette J, Casale J, Jones L. The separation of cocaine and phenyltetrahyroimidazothiazole mixtures. Microgram J 2013;10(2):12–6. [2] Tallarida C, Egan E, Alejo G, Raffa R, Tallarida R, Rawls S. Levamisole and cocaine synergism: a prevalent adulterant enhances cocaine's action in vivo. Neuropharmacology 2014;79:590–5. [3] Kouassi E, Caillé G, Léry L, Larivière L, Vézina M. Novel assay and pharmacokinetics of levamisole and p-hydroxylevamisole in human plasma and urine. Biopharm Drug Dispos 1986;7(1):71–89. http://dx.doi.org/10.1002/bdd.2510070110. [4] Roberts J, Chévez-Barrios P. Levamisole-induced vasculitis: a characteristic cutaneous vasculitis associated with levamisole-adulterated cocaine. Arch Pathol Lab Med 2015;139(8):1058–61. [5] Martinez-Taboada V, Bianco R, Gracia-Fuentes M, Rodriguez-Valverde V. Clinical features and outcome of 95 patients with hypersensitivity vasculitis. Am J Med 1997;102(2):186–91. [6] Arora N, Jain T, Bhanot R, Natesan S. Levamisole-induced leukocytoclastic vasculitis and neutropenia in a patient with cocaine use: an extensive case with necrosis of skin, soft tissue, and cartilage. Addict Sci Clin Pract 2012;7(1):19. [7] Lee K, Culpepper K, Kessler M. Levamisole-induced thrombosis: literature review and pertinent laboratory findings. J Am Acad Dermatol 2011;65(4):e128–9. http://dx.doi. org/10.1016/j.jaad.2011.05.023.
Please cite this article as: Graff N, et al, Purpuric skin eruption in an illicit drug user, Am J Emerg Med (2015), http://dx.doi.org/10.1016/ j.ajem.2015.11.055
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Case Report
Purpuric skin eruption in an illicit drug user Abstract A 36-year-old woman presented to the emergency department with 5 days of worsening painful bruising that started on her legs and spread to her torso and face. She reported recent use of heroin and cocaine. On examination, she was tachycardic with a nonblanching, painful, purpuric skin eruption on bilateral thighs, chest, upper arms, right cheek, and ears. Focal areas of necrosis without crepitance were noted. Emergency department workup ensued for possible drug-induced or bacterial coagulopathy with concern for purpura fulminans, disseminated intravascular coagulation, and/or necrotizing fasciitis. Empiric antibiotics were started, and patient was admitted to the progressive care unit where further workup confirmed levamisole-induced vasculitis. Levamisoleinduced vasculitis is an immune complex–mediated cutaneous small vasculitis syndrome associated with cocaine adulterated with levamisole. A characteristic palpable, painful, purpuric retiform rash with or without central necrosis is accompanied by typical laboratory findings of leukopenia, neutropenia, and positive autoantibodies[1,2]. Histologic features include microvascular fibrin thrombi and leukocytoclastic vasculitis of small vessels [1]. Treatment goals are preventing skin infection with broad-spectrum antibiotics and, if necessary, transfer to a burn center for definitive management of lesions. A 36-year-old white woman presented to the emergency department (ED) with 5 days of gradually worsening painful bruising that started on her legs and spread to her torso and face. She reported no trauma, recent illness, or fevers. Her history is pertinent for leukopenia, previous methicillin-resistant Staphylococcus aureus and hepatitis C virus infections, and intravenous heroin and crack cocaine use. She reported to the emergency physician last use of heroin 3 days ago and last smoking of cocaine 5 days ago. She was found to have sinus tachycardia at 128 beats per minute without murmur, blood pressure of 168/97, respiratory rate of 20 breaths per minute, and an oral temperature of 37.3°C. A nonblanching, painful, purpuric skin eruption was noted on bilateral thighs, chest, upper arms, right cheek and ears (Figs. 1 and 2). Focal areas of necrosis without crepitance were noted. Distal pulses were found to be equal and palpable in all extremities. She had benign chest and abdominal examinations. She had no measurable neurologic deficits. Emergency department workup ensued for possible drug-induced or bacterial coagulopathy with concern for purpura fulminans, disseminated intravascular coagulation (DIC), and/or necrotizing fasciitis. This resulted in evidence of elevated erythrocyte sedimentation rate, C-reactive protein, protime prolonged partial thromboplastin, Ddimer, and a microcytic anemia. Leukocytes and platelets were within normal limits. She had positive urine cocaine metabolites, methadone, opiates, and cannabinoids. Empiric treatment included high-
dose intravenous clindamycin and piperacillin/tazobactam and 2 L of 0.9% sodium chloride. Fentanyl 50 μg was provided for analgesia. Consultation was made to general surgery, and the patient was admitted to the hospitalist medical team for purpuric rash and coagulopathy without DIC. Purpuric skin lesions presenting to the ED raise concern for lifethreatening infections (meningococcemia, necrotizing fasciitis, and septic emboli), coagulopathies (DIC), and autoimmune disorders (vasculitis and Henoch-Schonlein purpura). Our patient was afebrile, and the history of recent intravenous drug use and cocaine use with distribution of the purpuric eruption raised suspicion for levamisole-induced vasculitis. However, infectious etiology should not be ruled out based on initial presentation and ED workup alone. Patients should be admitted on empiric antibiotics after appropriate hemodynamic stabilization for further diagnostics and treatment. Levamisole is a veterinary anthelminthic drug that has become an increasingly common additive to cocaine over the past decade. Levamisole was used as an immunomodulatory drug to treat colorectal cancer and various dermatologic pathologies before being withdrawn from the market in the United States in 1999 secondary to side effects including agranulocytosis. In 2013, the Drug Enforcement Administration reported that up to 70% of illicit cocaine samples in the United States contain levamisole [1]. It is proposed that levamisole is used as an additive secondary to its agonist activity at nicotinic receptors, potentiating the effects of cocaine [2]. The presence of levamisole can be tested in both plasma and urine, although results may be negative depending on last drug use as its plasma elimination half-life of 5 to 6 hours [3]. Levamisole-induced vasculitis is an immune complex–mediated cutaneous small vasculitis syndrome associated with cocaine adulterated with levamisole. The characteristic skin findings are a palpable, painful, purpuric retiform rash with or without central necrosis [4]. It is associated often with pharmaceuticals—penecillins, cephalosporins, sufonamides, phenytoin, and allopurinol—as well as with hepatitis B and C viruses, HIV, and chronic bacterial infections [5]. Skin manifestations occur on average 7 to 10 days after drug exposure and are predicated to the cheeks, nose, ears, trunk, and extremities [6]. Depending on the degree of necrosis, the lesions may result in surgical debridement, skin grafting and/or amputation [6]. Histologic features include microvascular fibrin thrombi and leukocytoclastic vasculitis of small vessels [4]. Typical laboratory findings include leukopenia, neutropenia, and positive autoantibodies including perineuclear and cytoplasmic Anti-Neutrophil Cytoplasmic Antibodies, antinuclear antibody, and lupus anticoagulant. [7] There is currently no standard treatment for levamisole-induced vasculitis. Treatment begins with stopping the inciting agent. As patients are often neutropenic, it is important to prevent infection of
0735-6757/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Graff N, et al, Purpuric skin eruption in an illicit drug user, Am J Emerg Med (2015), http://dx.doi.org/10.1016/ j.ajem.2015.11.055
2
N. Graff et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
Fig. 1. Painful purpura of the right ear with necrosis.
skin lesions with broad-spectrum antibiotic coverage. Depending on the extent of skin involvement and necrosis, patients may require transfer to a burn unit for definitive management of lesions. Our patient remained hemodynamically stable without evidence of DIC but continued to demonstrate a coagulopathy and developed leukopenia (3800/μL). No evidence of bacteremia, endocarditis, active hepatitis C virus, or antiphospholipid antibodies were identified. As suspected, levamisole was determined to be present in the patient's urine. Punch biopsied tissue revealed superficial and deep small vascular wall necrosis with neutrophilic infiltrate and luminal fibrin thrombi. This is compatible with levamisole-induced vasculitis likely from cocaine and/or heroin use, despite negative rheumatologic workup. The patient was transferred to a university hospital burn unit for symptomatic treatment due to diffuse skin loss over her lower extremities. She is back home and doing well with planned skin grafting once healed.
Nicholas Graff DO Kristen Whitworth DO ⁎ Christopher Trigger MD Lakeland Health Emergency Medicine Residency Program Lakeland Health, Saint Joseph, MI 49085 ⁎ Corresponding author. 2103 Langley Avenue, Saint Joseph, MI 49085 E-mail addressess: [email protected] [email protected] http://dx.doi.org/10.1016/j.ajem.2015.11.055
Fig. 2. Nonblanching, painful purpura on bilateral legs with hemorrhagic bullae and necrosis.
References [1] Mallette J, Casale J, Jones L. The separation of cocaine and phenyltetrahyroimidazothiazole mixtures. Microgram J 2013;10(2):12–6. [2] Tallarida C, Egan E, Alejo G, Raffa R, Tallarida R, Rawls S. Levamisole and cocaine synergism: a prevalent adulterant enhances cocaine's action in vivo. Neuropharmacology 2014;79:590–5. [3] Kouassi E, Caillé G, Léry L, Larivière L, Vézina M. Novel assay and pharmacokinetics of levamisole and p-hydroxylevamisole in human plasma and urine. Biopharm Drug Dispos 1986;7(1):71–89. http://dx.doi.org/10.1002/bdd.2510070110. [4] Roberts J, Chévez-Barrios P. Levamisole-induced vasculitis: a characteristic cutaneous vasculitis associated with levamisole-adulterated cocaine. Arch Pathol Lab Med 2015;139(8):1058–61. [5] Martinez-Taboada V, Bianco R, Gracia-Fuentes M, Rodriguez-Valverde V. Clinical features and outcome of 95 patients with hypersensitivity vasculitis. Am J Med 1997;102(2):186–91. [6] Arora N, Jain T, Bhanot R, Natesan S. Levamisole-induced leukocytoclastic vasculitis and neutropenia in a patient with cocaine use: an extensive case with necrosis of skin, soft tissue, and cartilage. Addict Sci Clin Pract 2012;7(1):19. [7] Lee K, Culpepper K, Kessler M. Levamisole-induced thrombosis: literature review and pertinent laboratory findings. J Am Acad Dermatol 2011;65(4):e128–9. http://dx.doi. org/10.1016/j.jaad.2011.05.023.
Please cite this article as: Graff N, et al, Purpuric skin eruption in an illicit drug user, Am J Emerg Med (2015), http://dx.doi.org/10.1016/ j.ajem.2015.11.055