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Systemic complications of levamisole toxicity

      To the Editor: We read with interest the articles by Chung et al
      • Chung C.
      • Tumeh P.C.
      • Birnbaum R.
      • Tan B.H.
      • Sharp L.
      • McCoy E.
      • et al.
      Characteristic purpura of the ears, vasculitis, and neutropenia–a potential public health epidemic associated with levamisole-adulterated cocaine.
      and Waller et al
      • Waller J.M.
      • Feramisco J.D.
      • Alberta-Wszolek L.
      • McCalmont T.H.
      • Fox L.P.
      Cocaine-associated retiform purpura and neutropenia: is levamisole the culprit?.
      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.
      • Chung C.
      • Tumeh P.C.
      • Birnbaum R.
      • Tan B.H.
      • Sharp L.
      • McCoy E.
      • et al.
      Characteristic purpura of the ears, vasculitis, and neutropenia–a potential public health epidemic associated with levamisole-adulterated cocaine.
      • Waller J.M.
      • Feramisco J.D.
      • Alberta-Wszolek L.
      • McCalmont T.H.
      • Fox L.P.
      Cocaine-associated retiform purpura and neutropenia: is levamisole the culprit?.
      • Lee K.C.
      • Culpepper K.
      • Kessler M.
      Levamisole-induced thrombosis: literature review and pertinent laboratory findings.
      Pathologically, it demonstrates small vessel vasculopathy or microthrombosis. Direct immunofluorescence is consistent with immune-complex mediated disease.
      Because levamisole contaminates approximately 69% of the US cocaine supply, dermatologists will likely continue to encounter this condition on inpatient consults and routine office visits.

      SAMHSA. Nationwide public health alert issued concerning life-threatening risk posed by cocaine laced with veterinary anti-parasite drug. September 21, 2009. Available from: URL:http://www.samhsa.gov/newsroom/advisories/090921vet5101.aspx. Accessed October 1, 2011.

      Therefore, we seek to highlight relevant associations of levamisole-induced vasculopathy published in nondermatologic literature and unrelated to skin manifestations.
      In addition to cocaine, levamisole has been found as a contaminant in heroin supplies seized and tested by the US Drug Enforcement Agency.

      SAMHSA. Nationwide public health alert issued concerning life-threatening risk posed by cocaine laced with veterinary anti-parasite drug. September 21, 2009. Available from: URL:http://www.samhsa.gov/newsroom/advisories/090921vet5101.aspx. Accessed October 1, 2011.

      Although levamisole-induced vasculopathy related to heroin has yet to be reported, health care providers should be alert to the possibility of this condition in a drug user with urine toxicology positive for opioids and negative for cocaine.
      Arthralgias affecting the large joints are the most common systemic manifestation, with 83% of patients affected, compared with only 61% of patients with a rash. Ear, nose, and throat involvement in the form of persistent rhinorrhea or recurrent sinusitis is present in 44%.
      • McGrath M.M.
      • Isakova T.
      • Rennke H.G.
      • Mottola A.M.
      • Laliberte K.A.
      • Niles J.L.
      Contaminated cocaine and antineutrophil cytoplasmic antibody-associated diseaes.
      However, nasal symptoms may also be related to method of cocaine use (insufflation or “snorting”) versus actual levamisole toxicity.
      A definitive immunologic profile has yet to be clarified. However, levamisole-induced vasculopathy characteristically reacts with human neutrophil elastase whereas classic immune vasculitis such as allergic granulomatosis (Churg-Strauss syndrome) or granulomatosis with polyangitis (Wegener granulomatosis) has no reactivity.
      • Walsh N.M.
      • Green P.J.
      • Burlingame R.W.
      • Pasternak S.
      • Hanly J.G.
      Cocaine-related retiform purpura: evidence to incriminate the adulterant, levamisole.
      One major disadvantage of this test is that many institutions require that samples are sent to a specialized laboratory; therefore, turnaround time is at least 1 week.
      Systemically, levamisole-induced vasculopathy has a theoretical risk of pulmonary hypertension,

      Karch SB, Mari F, Bartolini V, Bertol E. Aminorex poisoning in cocaine abusers. Int J Cardiol doi http://dx.doi.org/10.1016/j.ijcard.2011.06.105. Published online July 15, 2011.

      and a known risk of pulmonary hemorrhage.
      • McGrath M.M.
      • Isakova T.
      • Rennke H.G.
      • Mottola A.M.
      • Laliberte K.A.
      • Niles J.L.
      Contaminated cocaine and antineutrophil cytoplasmic antibody-associated diseaes.
      Levamisole was demonstrated to metabolize to aminorex through isolation of both compounds in urine samples of cocaine users.
      • Bertol E.
      • Mari F.
      • Milia M.G.
      • Politi L.
      • Furlanetto S.
      • Karch S.B.
      Determination of aminorex in human urine samples by GC-MS after use of levamisole.
      Aminorex is an amphetamine-like hallucinogenic with appetite suppression effects, potentially explaining the role of levamisole in adulterating illicit drugs. More importantly, aminorex ingestion during the late 1960s and early 1970s was responsible for a 5-year epidemic of idiopathic pulmonary hypertension in Europe, confined to countries where this medication was marketed as an anorectic. Incidence of pulmonary hypertension improved to normal levels when aminorex was withdrawn from the market.
      • Follath F.
      • Burkart F.
      • Schweizer W.
      Drug-induced pulmonary hypertension?.
      Pulmonary hemorrhage of unclear mechanism has been reported in 3 cases of levamisole-induced vasculopathy related to cocaine ingestion; none required intubation. Two cases of acute renal failure have also been attributed to this condition. One patient underwent a kidney biopsy, revealing pauci-immune focal necrotizing and crescentic glomerulonephritis.
      • McGrath M.M.
      • Isakova T.
      • Rennke H.G.
      • Mottola A.M.
      • Laliberte K.A.
      • Niles J.L.
      Contaminated cocaine and antineutrophil cytoplasmic antibody-associated diseaes.
      Despite improvement on systemic steroids, both patients progressed to chronic renal failure. An additional 6 patients have also been reported to have abnormal urine dipstick revealing hematuria without significant change in renal function.
      • McGrath M.M.
      • Isakova T.
      • Rennke H.G.
      • Mottola A.M.
      • Laliberte K.A.
      • Niles J.L.
      Contaminated cocaine and antineutrophil cytoplasmic antibody-associated diseaes.
      In addition to characteristics described in dermatology literature, levamisole-induced vasculopathy can present and involve a multitude of organ systems. We present this letter to alert dermatologists of the potential systemic complications associated with this condition.

      References

        • Chung C.
        • Tumeh P.C.
        • Birnbaum R.
        • Tan B.H.
        • Sharp L.
        • McCoy E.
        • et al.
        Characteristic purpura of the ears, vasculitis, and neutropenia–a potential public health epidemic associated with levamisole-adulterated cocaine.
        J Am Acad Dermatol. 2011; 65: 722-725
        • Waller J.M.
        • Feramisco J.D.
        • Alberta-Wszolek L.
        • McCalmont T.H.
        • Fox L.P.
        Cocaine-associated retiform purpura and neutropenia: is levamisole the culprit?.
        J Am Acad Dermatol. 2010; 63: 530-535
        • Lee K.C.
        • Culpepper K.
        • Kessler M.
        Levamisole-induced thrombosis: literature review and pertinent laboratory findings.
        J Am Acad Dermatol. 2011; 65: e128-e129
      1. SAMHSA. Nationwide public health alert issued concerning life-threatening risk posed by cocaine laced with veterinary anti-parasite drug. September 21, 2009. Available from: URL:http://www.samhsa.gov/newsroom/advisories/090921vet5101.aspx. Accessed October 1, 2011.

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        • Isakova T.
        • Rennke H.G.
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        • Laliberte K.A.
        • Niles J.L.
        Contaminated cocaine and antineutrophil cytoplasmic antibody-associated diseaes.
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        • Green P.J.
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        • Hanly J.G.
        Cocaine-related retiform purpura: evidence to incriminate the adulterant, levamisole.
        J Cutan Pathol. 2010; 37: 1212-1219
      2. Karch SB, Mari F, Bartolini V, Bertol E. Aminorex poisoning in cocaine abusers. Int J Cardiol doi http://dx.doi.org/10.1016/j.ijcard.2011.06.105. Published online July 15, 2011.

        • Bertol E.
        • Mari F.
        • Milia M.G.
        • Politi L.
        • Furlanetto S.
        • Karch S.B.
        Determination of aminorex in human urine samples by GC-MS after use of levamisole.
        J Pharm Biomed Anal. 2011; 55: 1186-1189
        • Follath F.
        • Burkart F.
        • Schweizer W.
        Drug-induced pulmonary hypertension?.
        Br Med J. 1971; 1: 265-266

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