Researchers have noted an increasing incidence in both cutaneous vasculopathy and levamisole-contaminated cocaine. Accordingly, these authors describe the diagnosis and treatment of lower extremity vasculitis caused by use of the adulterated narcotic.
Levamisole is an immunomodulator that veterinarians use as an anthelmintic agent. Physicians previously used levamisole to treat nephritic syndrome, autoimmune disorders, various cancers and some skin conditions in humans, but it was pulled from the market in the United States in 1999 secondary to leukopenia, agranulocytosis and skin vasculitis.1-8 Recently, levamisole has become more prevalent in the medical literature as a widespread adulterant to street cocaine. Reports from the Centers for Disease Control and Prevention (CDC) indicate 69 percent of cocaine is contaminated with levamisole with other sources estimating even higher rates.9,10 The incidence of cutaneous vasculopathy has experienced concordant growth in emergency department encounters and in the medical literature.10
In addition to finding pathognomonic cutaneous lesions of the nose and ears in those who have come into contact with levamisole, research from Maricopa Medical Center in Phoenix has indicated that 87.5 percent of cases involve lesions in the lower extremity, which is similar to other published data.10,11 Note that more than just “coming in contact” with the levamisole is required to produce the cutaneous lesions. Therefore, with the increased incidence and the implications for the lower extremities, foot and ankle specialists taking ER calls need to know how to recognize and treat these lesions.
Current Insights On Levamisole Use In Cocaine
The emergence of this cutaneous vasculopathic condition is relatively recent despite cocaine’s use since the 1800s. Currently, cocaine use is widespread in the United States. With an estimation of 2 to 5 million users, the United States is the world’s largest consumer of cocaine.12-14 In July 1999, the Drug Enforcement Administration reported that 69 percent of all cocaine seized at U.S. borders contained levamisole and at a concentration of about 10 percent.9 There have been various hypotheses regarding the addition of levamisole to cocaine but a recent study found that its metabolite aminorex is a powerful inhibitor of dopamine and norepinephrine reuptake, increases the release of serotonin and enhances synaptic catecholamine activity, which may enhance or prolong the effects of cocaine.15 As the presence of the contaminant and the frequency of cocaine use have increased, so have the associated numbers of levamisole-related adverse effects.
Agranulocytosis is not common. There are reportedly only 7.2 cases per 1 million in population per year, excluding patients with cancer and patients receiving cytotoxic drugs. However, agranulocytosis carries a risk for opportunistic infections and can be fatal in approximately 7 to 10 percent of cases.16 Cocaine use alone does not evoke agranulocytosis, neutropenia and characteristic vasculitis, but research has shown that these conditions can result from oral levamisole in up to 13 percent of patients using levamisole clinically.17
As more cases presented, various names for the condition emerged in the medical literature. These names included levamisole-induced cutaneous vasculopathy, levamisole-induced vasculitis, cocaine-induced pseudovasculitis, and levamisole-induced pseudovasculitis.Initial clinical findings are characterized by tender, purpuric lesions in retiform distribution with erythematous borders and areas of central necrosis, often accompanied by bullae (see Figures 1 and 2). Pediatric patients on longer-term oral levamisole use reportedly have non-specific rash or lichenoid eruptions with a documented latency of up to five years.18 The most commonly affected locus is the lower extremity (84 to 87.5 percent).11,19
Other differentials of florid vasculopathy in the extremities include septic emboli and cryoglobulinemia. Affected ears, specifically the helix, are pathognomonic due to the fact that they are uncommonly affected by other vasculitides and occur in 73 percent of patients (see Figure 3).11,20 Upper extremities and hands are also commonly affected. Other areas of the face include cheeks, nose and the oral region. The presence of cutaneous involvement of large areas of the lower extremities and ear involvement raises the index of suspicion for levamisole-induced vasculitis.
Key Pointers On Diagnosis And Treatment
The initial workup includes a thorough patient history including present or prior cocaine use, which raises the index of suspicion. Laboratory studies may include toxicology screen, complete blood cell (CBC) count, chest X-ray, cytoplasmic- or perinuclear-antineutrophil cytoplasmic antibody (c-ANCA or p-ANCA), antinuclear antibody, proteinase 3, anti-myeloperoxidase or direct immunofluorescence.
Laboratory findings show leukopenia (white blood cells < 4000/µL) and/or neutropenia (absolute neutrophil count <1500/µL) in 60 to 63 percent of cases.11,19 Though neutropenia is a published complication of levamisole causing agranulocytosis in 2.5 to 13 percent of patients on long-term use, it is not necessary to make the diagnosis.17,21
Direct confirmation of levamisole via gas chromatography and mass spectrometry requires urine samples within 5.6 hours of substance abuse. This shows high prevalence of levamisole with cocaine use (68 percent of 300 toxicology samples) but is not always feasible due to the half-life of levamisole and poor availability of labs equipped to perform gas chromatography.22,23 If this window of time has elapsed, antihuman neutrophil elastase (anti-HNE) can help confirm levamisole/cocaine, differentiating it from Wegener’s granulomatosis.11,19,24
Small-vessel leukocytoclastic vasculitis may occur in association with a variety of conditions including sepsis, cryoglobulinemia, drug allergy, Henoch-Schonlein purpura, connective tissue disease, systemic vasculitis, inflammatory bowel disease, Streptococcus infection, viral hepatitis, other infections, systemic malignancy, and other systemic disorders. It is therefore imperative to differentiate the cutaneous presentations of levamisole-contaminated cocaine use from that of true vasculitic diseases such as Wegener’s granulomatosis, cutaneous polyarteritis nodosa and Churg-Strauss syndrome because the treatments are remarkably different.
The onset in classical vasculitic diseases is more gradual. Histological analysis of skin biopsies shows thrombotic vasculopathy, vasculitis or a combination of thrombosis with vasculitis. With rare exceptions, granulomas typically occur with Wegener’s granulomatosis and Churg-Strauss syndrome and are not present in levamisole/cocaine-induced cutaneous lesions.20,25 Antineutrophil cytoplasmic antibody testing, by either immunofluorescence or enzyme-linked immunosorbent assay (ELISA), usually shows more frequent positivity of p-ANCA than c-ANCA, or a combination of the two. Though not specific, positive p-ANCA, anti-myeloperoxidase and proteinase 3 are consistent with levamisole-induced vasculitis.11,26 The anti-HNE is a very high indicator of levamisole involvement. A 2012 review of all published cases and reports to date found 100 percent correlation with levamisole-contaminated cocaine use in a small accumulative cohort.11 Researchers suspect levamisole to cause positive lupus anticoagulant antibodies in some patients.18,20,27 If a toxicology screen, anti-HNE and/or levamisole screens are positive, one should suspect levamisole-induced vasculitis.11,19,20,24
When mild lesions present for the first time and patients abandon cocaine use, the skin lesions are short-lived, resolving usually in a matter of weeks by secondary intention. Treatment with topical steroids is controversial. Advanced lesions may require more aggressive tangential excision and debridement with temporary allograft or xenograft in preparation for appropriate permanent coverage via split thickness autograft. Judicious timing is paramount to ensure that antibody profiles have returned to baseline prior to skin grafting. Continued vasculitic activity carries a risk of continued tissue necrosis and therefore graft failure.
Lower extremity specialists must be aware of this emerging condition as the presence of levamisole-contaminated cocaine becomes more widespread and increased use translates into growing patient encounters. It is crucial to distinguish the untoward effects of levamisole from other cutaneous vasculidities and the general thought process in management and, if indicated, surgical treatment.
Dr. Ellis is a third-year resident at Maricopa Medical Center in Phoenix.
Dr. Fishco is board-certified in foot surgery and reconstructive rearfoot and ankle surgery by the American Board of Podiatric Surgery. He is a Fellow of the American College of Foot and Ankle Surgeons, and is a faculty member of the Podiatry Institute. Dr. Fishco is in private practice in Phoenix.
1. Ching JA, Smith DJ Jr. Levamisole-induced necrosis of skin, soft tissue, and bone: case report and review of literature. J Burn Care Res. 2012; 33(1):e1-5.
2. Donia AF, Ammar HM, El-Agroudy A, Moustafa F, Sobh MA. Long-term results of two unconventional agents in steroid-dependent nephrotic children. Pediatr Nephrol. 2005; 20(10):1420-5.
3. Abdul-Karim R, Ryan C, Rangel C, Emmett M. Levamisole-induced vasculitis. Proc (Bayl Univ Med Cent). 2013; 26(2):163-165.
4. Amery WK, Bruynseels JP. Levamisole, the story and the lessons. Int J Immunopharmacol. 1992; 14(3):481-6.
5. Runge LA, Pinals RS, Lourie SH, Tomar RH. Treatment of rheumatoid arthritis with levamisole. A controlled trial. Arthritis Rheum. 1977; 20(8):1445-8.
6. Christensen KD. Treatment of seronegative spondylarthritis with levamisole: a double-blind placebo-controlled study. Int J Immunopharmacol. 1979; 1(2):147-50.
7. Tanphaichitr P, Tanphaichitr D, Sureeratanan J, Chatasingh S. Treatment of nephrotic syndrome with levamisole. J Pediatr. 1980; 96(3 Pt 1):490-3.
8. Chang A, Osterloh J, Thomas J. Levamisole: a dangerous new cocaine adulterant. Clin Pharmacol Ther. 2010; 88(3):408-11.
9. Centers for Disease Control and Prevention (CDC). Agranulocytosis associated with cocaine use - four States, March 2008-November 2009. MMWR Morb Mortal Wkly Rep. 2009; 58(49):1381-5.
10. Dan Quan, MD, Toxicologist at Maricopa Medical Center, personal communication, May 2013.
11. Pearson T, Bremmer M, Cohen J, Driscoll M. Vasculopathy related to cocaine adulterated with levamisole: A review of the literature. Dermatol Online J. 2012; 18(7):1.
12. Vagi SJ, Sheikh S, Brackney M, et al. Passive multistate surveillance for neutropenia after use of cocaine or heroin possibly contaminated with levamisole. Ann Emerg Med. 2013; 61(4):468-74.
13. Walsh NM, Green PJ, Burlingame RW, Pasternak S, Hanly JG. Cocaine-related retiform purpura: evidence to incriminate the adulterant, levamisole. J Cutan Pathol. 2010; 37(12):1212-9.
14. Field Listing – Illicit drugs (by country). Available at www.cia.gov . Accessed May 7, 2014.
15. Hofmaier T, Luf A, Seddik A. Aminorex, a metabolite of the cocaine adulterant levamisole, exerts amphetamine like actions at monoamine transporters. Neurochem Int. 2013; 73:32-41.
16. Ibanez L, Vidal X, Ballarin E, Laporte JR. Population-based drug-induced agranulocytosis. Arch Intern Med. 2005; 165(8):869-74.
17. Thompson JS, Herbick JM, Klassen LW, et al. Studies on levamisole--induced agranulocytosis. Blood. 1980; 56(3):388-96.
18. Rongioletti F, Ghio L, Ginevri F, 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(5):948-51.
19. Arora NP. Cutaneous vasculopathy and neutropenia associated with levamisole-adulterated cocaine. Am J Med Sci. 2013; 345(1):45-51.
20. Lutfy J, Noland ME, Jarmuske M. How to spot cocaine-induced pseudovasculitis. Ann Plast Surg. 2013; 70(3):375-8.
21. Chai PR, Bastan W, Machan J, Hack JB, Babu KM. Levamisole exposure and hematologic indices in cocaine users. Acad Emerg Med. 2011; 18(11):1141-7.
22. Kouassi E, Caille G, Lery L, Lariviere L, Vezina M. Novel assay and pharmacokinetics of levamisole and p-hydroxylevamisole in human plasma and urine. Biopharm Drug Dispos. 1986; 7(1):71-89.
23. Buchanan JA, Heard K, Burbach C, Wilson ML, Dart R. Prevalence of levamisole in urine toxicology screens positive for cocaine in an inner-city hospital. JAMA. 2011; 305(16):1657-8.
24. Wiesner O, Russell KA, Lee AS, 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(9):2954-65.
25. Gertner E, Hamlar D. Necrotizing granulomatous vasculitis associated with cocaine use. J Rheumatol. 2002; 29(8):1795-7.
26. McGrath MM, Isakova T, Rennke HG, Mottola AM, Laliberte KA, Niles JL. Contaminated cocaine and antineutrophil cytoplasmic antibody-associated disease. Clin J Am Soc Nephrol. 2011; 6(12):2799-805.
27. Zhu NY, Legatt DF, Turner AR. Agranulocytosis after consumption of cocaine adulterated with levamisole. Ann Intern Med. 2009; 150(4):287-9.