Cocaine-associated retiform purpura and neutropenia: Is levamisole the culprit?

Abstract

To the Editor: We describe two patients with neutropenia and retiform purpura associated with cocaine use and alert clinicians to the possible emerging public health threat of levamisole-contaminated cocaine.Case 1 was a 38-year-old woman with hepatitis C, remote miscarriage, and active polysubstance abuse who was admitted for methicillin-resistant Staphylococcus aureus endocarditis. A toxicology screen performed on admission was positive for cocaine, opiates, and benzodiazepines. She developed a deep venous thrombosis on her right lower extremity that was initially treated with heparin and an appropriate bridge to warfarin. On day 27 (day 12 of warfarin), she developed multiple discrete, stellate, purpuric macules, papules, and plaques with a bright erythematous border on her pinna, earlobes, cheeks, right breast, and bilateral proximal upper and lower extremities (Fig 1, A-C). Concomitant unexplained episodic tachycardia and neutropenia were noted.Skin biopsy specimens revealed leukocytoclastic vasculitis with mural fibrin deposition, neutrophilic infiltrate, nuclear dust, and extravasated erythrocytes involving superficial small vessels with pauciinflammatory luminal thrombosis in a few vessels (Fig 1, G and H). Synchronous tests revealed positive platelet factor IV antibody (but negative serotonin release assay), mixing studies (noncorrecting), lupus anticoagulant, and Russell viper venom time. Antineutrophil cytoplasmic antibodies (ANCAs) directed against proteinase-3 (PR-3) were 39.2 EU/mL (normal, p-ANCA) positive and most closely resembles Wegener granulomatosis with nasal septal midline destruction and/or acrally distributed palpable purpura with vasculitis of small- and medium-sized dermal vessels.1Trimarchi M. Gregorini G. Facchetti F. Morassi M.L. Manfredini C. Maroldi R. et al.Cocaine-induced midline destructive lesions: clinical, radiographic, histopathologic, and serologic features and their differentiation from Wegener granulomatosis.Medicine (Baltimore). 2001; 80: 391-404Crossref PubMed Scopus (110) Google Scholar, 2Neynaber S. Mistry-Burchardi N. Rust C. Samtleben W. Burgdorf W.H. Seitz M.A. et al.PR3-ANCA-positive necrotizing multi-organ vasculitis following cocaine abuse.Acta Dermatol Venereol. 2008; 88: 594-596PubMed Google Scholar, 3Wiesner O. Russell K.A. Lee A.S. Jenne D.E. Trimarchi M. Gregorini et al.Antineutrophil cytoplasmic antibodies reacting with human neutrophil elastase as a diagnostic marker for cocaine-induced midline destructive lesions but not autoimmune vasculitis.Arthritis Rheum. 2004; 50: 2954-2965Crossref PubMed Scopus (169) Google Scholar Retiform purpura related to cocaine-induced ANCA-positive disease has not been reported.Table INarrowed differential diagnosis for our patients with description of differentiating clinical and pathologic featuresClinicalConditionMorphologyTimingDistributionPathologic featuresLaboratory valuesAntineutrophil cytoplasmic (ANCA) associated vasculitidesPalpable purpura, retiform purpura, nodules, ulcers, papulonecrotic lesions, and oral ulcersMPA can be acutely triggered by drugs/infectionFace, extremities, scalp, and oral/nasal mucosa (WG); many systemic associations, predominantly in the lungs and kidneysMPA: segmental necrotizing vasculitis of capillaries/venules/medium-sized vessels; LCVp-ANCA (anti-MPO, 60%); c-ANCA (anti-PR3; 30%); check urinalysis for glomerulonephritisWG relapses can be triggered by Staphylococcus aureus carriageWG: necrotizing granulomatous vasculitis; LCVc-ANCA (anti-PR3, 80%); p-ANCA (anti-MPO, 10%); check urinalysis for glomerulonephritis; 50% have positive rheumatoid factorCSS skin findings typically not seen until the third phase of the disease and are chronic; can be triggered by infection and leukotriene inhibitorsCSS: eosinophils, extravascular granulomatous inflammation, and necrotizing vasculitis of small- and medium-sized vesselsp-ANCA (anti-MPO, 55-60%); c-ANCA (anti-PR3, 10-15%); eosinophiliaAntiphospholipid antibody syndromeVariable; livedo±retiform purpura, atrophie blanche, leg ulcers, digital gangrene, cutaneous necrosis, splinter hemorrhages, and anetodermaAcute and chronic forms existLivedo reticularis is widespread; atrophie blanche around malleoli; retiform purpura on the upper and lower extremities, ear helices, cheeks, trunk, and forehead; anetoderma on the proximal extremities and trunkEarly lesions show noninflammatory thrombosis of small- and medium-sized dermal vesselsPositive lupus anticoagulant, anticardiolipin antibody, or anti-B2 glycoprotein antibody on 2 occasions at least 12 wks apartCocaine-induced purpuraRetiform purpura (current case); ulcers8Powell J. Grech H. Holder J. A boy with cutaneous necrosis occurring during treatment with levamisole.Clin Exp Dermatol. 2002; 27: 32-33Crossref PubMed Scopus (34) Google Scholar; persistent erythematous, partially hemorrhagic, infiltrated, confluent wheals10King County Web site. Health advisory: agranulocytosis caused by levamisole-contaminated cocaine. July 15, 2009. Available from: http://www.kingcounty.gov/healthservices/health/communicable/providers/2009/advisory090715.aspx. Accessed September 24, 2009Google Scholar; and palpable purpura19Acute in onsetDiffuse; face, scalp, trunk, extremitiesLCV and bland thrombosis; diffuse neutrophilic infiltrate; LCV of small vessels only or small- and medium-sized vesselsUrine toxicology;ANCA (anti-PR3; anti-MPO)Cryoglobulinemias Mixed (Types II/III)Predominantly palpable purpuraChronicLower extremities; also associated with peripheral neuropathy, arthralgias, hepatic disease, and membranoproliferative glomerulonephritisLCV; direct immunofluorescence shows IgM and/or C3 in vascular pattern in papillary dermisPositive for type II/III (mixed) cryoglobulins; association with hepatitis C >> hepatitis B, HIV; positive rheumatoid factor (70%) Type IRaynaud phenomenon, retiform purpura, livedo, and gangreneCan be cold-induced, acuteAcral sites (fingers, toes, and ears) predominateBland hyaline or red-cell occlusion of vessels, eosinophilic thrombi within small dermal vessels±necrosisAssociation with underlying plasma cell dyscrasia or lymphoproliferative disorderDICPetechiae → ecchymoses → hemorrhagic bullae → gangreneAcute and chronic forms existUsually symmetrical on extremities, often distal (ie, lips, ears, nose, and genitals), and on sites of venipuncture/surgeryFibrin deposits ("red") clots in dermal vessels; sparse inflammatory infiltratesElevated prothrombin time/partial thromboplastin time/International Normalized Ratio; low fibrinogen; low platelets; increased fibrin degradation products; schistocytes on peripheral blood smearHeparin-induced thrombocytopeniaTender, sharply demarcated retiform purpuraTypically 5-10 days after starting heparinInjection sites or sites distal to infusions, especially lower extremitiesPlatelet deposits ("white") clots in dermal vessels; noninflammatoryThrombocytopenia variable, may be late, NOT necessary for diagnosis; positive platelet factor IV antibody and serotonin release assay"Septic" vasculitisRetiform purpura or palpable purpuraTypically acute onsetUsually predominantly acralSevere pandermal vasculitis (small- and/or medium-sized vessels) with neutrophil and bacteria-containing thrombi, extravascular neutophilia, neutrophilic exocytosis, and papillary dermal edema; may show organism in vessel; may only show noninflammatory thrombotic purpuraWorkup for systemic infectionWarfarin skin necrosisErythematous and retiform purpura plaques, hemorrhagic bullae, full-thickness necrosis3-6 days after starting warfarinBreast, buttocks, and thighs (favors fatty areas)Fibrin deposits ("red") clots in dermal vessels; noninflammatory arterial thrombi commonProtein C may be relatively low (temporary hypercoagulable state); risk factors include proteins C or S or antithrombin III deficiencyANCA, Antineutrophil cytoplasmic antibody; CSS, Churg–Strauss syndrome; c-ANCA, cytoplasmic ANCA; DIC, disseminated intravascular coagulation; LCV, leukocytoclastic vasculitis; MPA, microscopic polyangiitis; MPO, myeloperoxidase; p-ANCA, perinuclear ANCA; PR3, proteinase 3; WG, Wegner granulomatosis. Open table in a new tab The uniqueness of retiform purpura in the setting of cocaine use insinuated levamisole as a possible culprit, because it is currently a contaminant in more than 70% of the US cocaine supply4US Department of Justice, Drug Enforcement Administration. Cocaine signature program report, January-October 2008. Internal document.Google Scholar, 5Hitt E. Cocaine laced with levamisole increasing, poses risk for aganulocytosis. Medscape. Available from: http://www.medscape.com/viewarticle/709451?src=rss. Accessed September 24, 2009.Google Scholar and has been shown to cause agranulocytosis6Levamisole. In: DRUGDEX system. Greenwood Village, CO: Thomson Healthcare. Available from: www.thomsonhc.com/hcs/librarian. Accessed January 13, 2009.Google Scholar and purpuric eruptions7Rongioletti 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: 948-951Crossref PubMed Scopus (126) Google Scholar, 8Powell J. Grech H. Holder J. A boy with cutaneous necrosis occurring during treatment with levamisole.Clin Exp Dermatol. 2002; 27: 32-33Crossref PubMed Scopus (34) Google Scholar in association with lupus anticoagulant positivity and/or c- or p-ANCA positivity. Complete clinical resolution of skin lesions occurs 2 to 3 weeks after stopping levamisole and serologies normalize within 2 to 14 months. Skin biopsy specimens from purpuric plaques in children given levamisole for nephrotic syndrome reveal thrombotic vasculitis, leukocytoclastic vasculitis, and/or vascular occlusion.7Rongioletti 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: 948-951Crossref PubMed Scopus (126) Google Scholar The presence of both leukocytoclastic vasculitis and vascular occlusion was noted in case 1 (Fig 1, G and H) and supported the role of levamisole contamination in this case. Life-threatening agranulocytosis and a positive lupus anticoagulant have been recently identified secondary to levamisole adulteration of cocaine.5Hitt E. Cocaine laced with levamisole increasing, poses risk for aganulocytosis. Medscape. Available from: http://www.medscape.com/viewarticle/709451?src=rss. Accessed September 24, 2009.Google Scholar, 9Zhu N.Y. Legatt D.F. Turner A.R. Agranulocytosis after consumption of cocaine adulterated with levamisole.Ann Intern Med. 2009; 150: 287-288Crossref PubMed Scopus (125) Google Scholar, 10King County Web site. Health advisory: agranulocytosis caused by levamisole-contaminated cocaine. July 15, 2009. Available from: http://www.kingcounty.gov/healthservices/health/communicable/providers/2009/advisory090715.aspx. Accessed September 24, 2009Google ScholarWe acknowledge that our suspicion of levamisole contamination was retrospective. However, detection of levamisole is challenging, because specific testing is necessary but not routinely available; levamisole's half-life is so short (5.6 hours) that only 2% to 5% of the parent drug is detected in urine9Zhu N.Y. Legatt D.F. Turner A.R. Agranulocytosis after consumption of cocaine adulterated with levamisole.Ann Intern Med. 2009; 150: 287-288Crossref PubMed Scopus (125) Google Scholar; and the sensitivity of available testing is low.Our patients' retiform purpura, histopathology, neutropenia, lupus anticoagulant and ANCA positivity, and temporal association with cocaine use are strongly suggestive of exposure to levamisole. Physicians should be aware of the ubiquitous contamination of cocaine with levamisole and the potentially dangerous clinical manifestations of levamisole exposure. To the Editor: We describe two patients with neutropenia and retiform purpura associated with cocaine use and alert clinicians to the possible emerging public health threat of levamisole-contaminated cocaine. Case 1 was a 38-year-old woman with hepatitis C, remote miscarriage, and active polysubstance abuse who was admitted for methicillin-resistant Staphylococcus aureus endocarditis. A toxicology screen performed on admission was positive for cocaine, opiates, and benzodiazepines. She developed a deep venous thrombosis on her right lower extremity that was initially treated with heparin and an appropriate bridge to warfarin. On day 27 (day 12 of warfarin), she developed multiple discrete, stellate, purpuric macules, papules, and plaques with a bright erythematous border on her pinna, earlobes, cheeks, right breast, and bilateral proximal upper and lower extremities (Fig 1, A-C). Concomitant unexplained episodic tachycardia and neutropenia were noted. Skin biopsy specimens revealed leukocytoclastic vasculitis with mural fibrin deposition, neutrophilic infiltrate, nuclear dust, and extravasated erythrocytes involving superficial small vessels with pauciinflammatory luminal thrombosis in a few vessels (Fig 1, G and H). Synchronous tests revealed positive platelet factor IV antibody (but negative serotonin release assay), mixing studies (noncorrecting), lupus anticoagulant, and Russell viper venom time. Antineutrophil cytoplasmic antibodies (ANCAs) directed against proteinase-3 (PR-3) were 39.2 EU/mL (normal, p-ANCA) positive and most closely resembles Wegener granulomatosis with nasal septal midline destruction and/or acrally distributed palpable purpura with vasculitis of small- and medium-sized dermal vessels.1Trimarchi M. Gregorini G. Facchetti F. Morassi M.L. Manfredini C. Maroldi R. et al.Cocaine-induced midline destructive lesions: clinical, radiographic, histopathologic, and serologic features and their differentiation from Wegener granulomatosis.Medicine (Baltimore). 2001; 80: 391-404Crossref PubMed Scopus (110) Google Scholar, 2Neynaber S. Mistry-Burchardi N. Rust C. Samtleben W. Burgdorf W.H. Seitz M.A. et al.PR3-ANCA-positive necrotizing multi-organ vasculitis following cocaine abuse.Acta Dermatol Venereol. 2008; 88: 594-596PubMed Google Scholar, 3Wiesner O. Russell K.A. Lee A.S. Jenne D.E. Trimarchi M. Gregorini et al.Antineutrophil cytoplasmic antibodies reacting with human neutrophil elastase as a diagnostic marker for cocaine-induced midline destructive lesions but not autoimmune vasculitis.Arthritis Rheum. 2004; 50: 2954-2965Crossref PubMed Scopus (169) Google Scholar Retiform purpura related to cocaine-induced ANCA-positive disease has not been reported. ANCA, Antineutrophil cytoplasmic antibody; CSS, Churg–Strauss syndrome; c-ANCA, cytoplasmic ANCA; DIC, disseminated intravascular coagulation; LCV, leukocytoclastic vasculitis; MPA, microscopic polyangiitis; MPO, myeloperoxidase; p-ANCA, perinuclear ANCA; PR3, proteinase 3; WG, Wegner granulomatosis. The uniqueness of retiform purpura in the setting of cocaine use insinuated levamisole as a possible culprit, because it is currently a contaminant in more than 70% of the US cocaine supply4US Department of Justice, Drug Enforcement Administration. Cocaine signature program report, January-October 2008. Internal document.Google Scholar, 5Hitt E. Cocaine laced with levamisole increasing, poses risk for aganulocytosis. Medscape. Available from: http://www.medscape.com/viewarticle/709451?src=rss. Accessed September 24, 2009.Google Scholar and has been shown to cause agranulocytosis6Levamisole. In: DRUGDEX system. Greenwood Village, CO: Thomson Healthcare. Available from: www.thomsonhc.com/hcs/librarian. Accessed January 13, 2009.Google Scholar and purpuric eruptions7Rongioletti 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: 948-951Crossref PubMed Scopus (126) Google Scholar, 8Powell J. Grech H. Holder J. A boy with cutaneous necrosis occurring during treatment with levamisole.Clin Exp Dermatol. 2002; 27: 32-33Crossref PubMed Scopus (34) Google Scholar in association with lupus anticoagulant positivity and/or c- or p-ANCA positivity. Complete clinical resolution of skin lesions occurs 2 to 3 weeks after stopping levamisole and serologies normalize within 2 to 14 months. Skin biopsy specimens from purpuric plaques in children given levamisole for nephrotic syndrome reveal thrombotic vasculitis, leukocytoclastic vasculitis, and/or vascular occlusion.7Rongioletti 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: 948-951Crossref PubMed Scopus (126) Google Scholar The presence of both leukocytoclastic vasculitis and vascular occlusion was noted in case 1 (Fig 1, G and H) and supported the role of levamisole contamination in this case. Life-threatening agranulocytosis and a positive lupus anticoagulant have been recently identified secondary to levamisole adulteration of cocaine.5Hitt E. Cocaine laced with levamisole increasing, poses risk for aganulocytosis. Medscape. Available from: http://www.medscape.com/viewarticle/709451?src=rss. Accessed September 24, 2009.Google Scholar, 9Zhu N.Y. Legatt D.F. Turner A.R. Agranulocytosis after consumption of cocaine adulterated with levamisole.Ann Intern Med. 2009; 150: 287-288Crossref PubMed Scopus (125) Google Scholar, 10King County Web site. Health advisory: agranulocytosis caused by levamisole-contaminated cocaine. July 15, 2009. Available from: http://www.kingcounty.gov/healthservices/health/communicable/providers/2009/advisory090715.aspx. Accessed September 24, 2009Google Scholar We acknowledge that our suspicion of levamisole contamination was retrospective. However, detection of levamisole is challenging, because specific testing is necessary but not routinely available; levamisole's half-life is so short (5.6 hours) that only 2% to 5% of the parent drug is detected in urine9Zhu N.Y. Legatt D.F. Turner A.R. Agranulocytosis after consumption of cocaine adulterated with levamisole.Ann Intern Med. 2009; 150: 287-288Crossref PubMed Scopus (125) Google Scholar; and the sensitivity of available testing is low. Our patients' retiform purpura, histopathology, neutropenia, lupus anticoagulant and ANCA positivity, and temporal association with cocaine use are strongly suggestive of exposure to levamisole. Physicians should be aware of the ubiquitous contamination of cocaine with levamisole and the potentially dangerous clinical manifestations of levamisole exposure. Systemic complications of levamisole toxicityJournal of the American Academy of DermatologyVol. 67Issue 4PreviewTo the Editor: We read with interest the articles by Chung et al1 and Waller et al2 regarding the recently characterized syndrome of levamisole-induced vasculopathy. Cutaneously, this condition is associated with hemorrhagic bullae, retiform purpura, and necrosis. Bilateral ear helix involvement is common. Systemically, it characteristically presents with mild to severe neutropenia and positivity for perinuclear antineutrophil cytoplasmic antibody.1-3 Pathologically, it demonstrates small vessel vasculopathy or microthrombosis. Full-Text PDF