What is levamisole?
Levamisole is an anthelmintic medication currently only licensed in the United States and Canada for use in veterinary medicine, due to reports of adverse events including agranulocytosis (severely decreased white blood cell count), facial retiform purpura and serological abnormalities in humans.
Levamisole was used in humans in the 1960s as a prescribed appetite suppressant [1,2]. It was also used as an immune-modulating agent for treatment of lichen planus, paediatric nephrotic syndrome and rheumatoid arthritis after its approval by the US Food and Drug Administration in 1991.
What is levamisole-adulterated cocaine vasculopathy?
Cutaneous vasculopathy associated with levamisole-adulterated (contaminated) cocaine is an emerging syndrome characterised by a retiform purpura around the ears, the presence of anti-neutrophil cytoplasmic autoantibody (ANCA), and leukopenia [3,4].
Levamisole-adulterated cocaine vasculopathy was first described in the late 2000s following an increase in the lacing of cocaine with levamisole.
Who gets levamisole-adulterated cocaine vasculopathy?
In 2010, 80% of cocaine seized by US authorities was levamisole-adulterated [2,5]. Levamisole-adulterated cocaine vasculopathy is exclusively reported in cocaine users, more often with chronic use and in those smoking and snorting contaminated cocaine [6,7]. It can also occur when cocaine is injected.
The average age of patients at presentation is 44 years old . Levamisole-adulterated cocaine vasculopathy is more prevalent in women, at a ratio of 1:3 . Patients carrying the major histocompatibility complex (MHC) class 1 human leukocyte antigen (HLA)–B27 are at risk of developing levamisole related agranulocytosis .
What causes levamisole-adulterated cocaine vasculopathy?
The exact cause of levamisole-adulterated cocaine vasculopathy is unknown. It is associated with immune dysfunction.
- The inflammation of small– and medium–sized blood vessels in the skin has a different serological profile from pure cocaine-related vasculopathy, and is probably due to the levamisole component [1,2,7].
- One of the three products of levamisole breakdown, known as 6-phenyl-2,3-dihydroimidazo(2,1b)-thiazole, has lymphocyte-stimulating effects, which could play a role in pathogenesis .
- Levamisole may cause production of neutrophil extracellular traps (NETs) which are released from neutrophils during cell death from a variety of stimuli. NETs activate the adaptive immune response, leading to the production of ANCAs .
What are the clinical features of levamisole-adulterated cocaine vasculopathy?
Retiform purpura are tender dusky purple papules, with a non-blanching centre and an erythematous, irregular border . They appear about 4 days after using levamisole-adulterated cocaine. The papules tend to be bilateral and symmetrically distributed. Affected sites may include:
- Ears (lobe or outer rim)
- Tip of the nose
- Malar region of the cheeks
- Proximal extremities
- Buttock and lower extremities [9–11].
Systemic features of levamisole-adulterated cocaine vasculopathy may include:
- Arthralgia 
- Rhinorrhoea (runny nose)
- Sinusitis .
Upper respiratory tract manifestations include:
These are related to low white blood cell count (neutropenia) .
Constitutional symptoms include :
- Night sweats
- Weight loss
What are the complications of levamisole-adulterated cocaine vasculopathy?
- Blisters, which can lead to necrosis [7,11]
- Self-amputation of ears and digits 
- Secondary bacterial skin infection [1,10]
- Scarring at the sites of confluent purpura, bullae and necrosis; if necrosis is extensive, surgical amputation may be needed .
- Neutropenia and agranulocytosis, which can lead to systemic bacterial infections or fungal infections, have been noted. 
- Acute renal failure and cases of biopsy-proven pauci-immune glomerulonephritis have been recorded. One case progressed to chronic renal failure .
- At least three cases of pulmonary hypertension have been reported in patients with levamisole-adulterated cocaine vasculopathy .
- One case of pulmonary haemorrhage has been reported .
There has been a case report of concurrent levamisole-adulterated cocaine vasculopathy and cocaine-induced midline destructive lesions (CIMDLs) .
How is levamisole-adulterated cocaine vasculopathy diagnosed?
The diagnosis of levamisole-adulterated cocaine vasculopathy should be considered in individuals with current cocaine use, painful joints, and retiform purpura. There is no single confirmatory test.
Serology is positive with high titres of perinuclear ANCA (p-ANCA, 84%), antinuclear, lupus anticoagulant, anti-human neutrophil elastase, anti-myeloperoxidase (100%), anti-proteinase 3 (50%) and anti-phospholipid antibodies (63%) [8,10].
- Leukopenia occurs in 28% of patients .
- Neutropenia (< 1.5x109granulocytes/L) and agranulocytosis (< 0.5 x 109 granulocytes/L) occur in 2.5–13% of patients .
To ensure urine toxicology is positive, a sample of urine must be collected within 4 days of the last use of cocaine .
- Urine levamisole is detected by gas chromatography mass spectrometry and must be performed within 48 hours. It is only detected in 13% of patients with suspected levamisole-adulterated cocaine vasculopathy [6,12].
- Urinalysis may reveal proteinuria, haematuria and cellular casts [2,12].
There are two classic features seen in levamisole-adulterated cocaine vasculopathy:
- Leukocytoclastic vasculitis of small vessels 
- Multiple fibrin thrombi within small vessels in the superficial and deep dermis .
Both findings are usually present, but fibrin thrombi are the more consistent feature . Direct immunofluorescence is nonspecific. It can show immunoglobulin (Ig) A, IgM, C3 and intravascular fibrin .
Grading disease severity
A grading system based on cutaneous manifestations for disease severity has been proposed, stratifying disease into mild, moderate and severe . The authors noted that, in stage 3 disease, withdrawal of levamisole–adulterated cocaine alone will not result in cutaneous resolution .
Stage 1 (Mild)
- Mild purpura with no necrosis
- Discontinuation of LAC, spontaneous healing expected
Stage 2 (Moderate)
- Purpuric patches/plaques with no ulceration
- Discontinuation of LAC, spontaneous healing expected
Stage 3 (Severe)
- Confluent purpura with or without necrosis
- Discontinuation of LAC, hospital admission with debridement and grafting warranted after observing for 72 hours.
- Withdrawal of levamisole-adulterated cocaine alone will not result in cutaneous resolution.
NOTE: early debridement was associated with the development of new lesions likely due to pathergy phenomenon.
What is the differential diagnosis for levamisole-adulterated cocaine vasculopathy?
Levamisole-adulterated cocaine use can be confused with other forms of cutaneous vasculitis; these include:
- ANCA-positive associated vasculitides such as granulomatosis with polyangiitis and microscopic polyangiitis
- Small–sized vasculitis and medium–sized vasculitis
- Anti–phospholipid syndrome
Anti–phospholipid antibodies, lupus anticoagulant, high-titre ANCAs and multiple constituents of neutrophilic granules help to differentiate levamisole–adulterated cocaine vasculopathy from other ANCA-positive vasculitides.
The relative lack of end organ damage differentiates levamisole-adulterated cocaine vasculopathy from true autoimmune diseases [3,5,7,11].
Infections that can cause purpura include:
- Disseminated pseudomonal infection (ecthyma gangrenosum)
- Staphylococcal bacteraemia (the most common cause of sepsis)
- Angio-invasive deep fungal infections
- Septic emboli.
For patients undergoing anticoagulant therapy, warfarin–induced skin necrosis, disseminated intravascular coagulation or heparin–induced thrombocytopenia should be considered [3,7,8]. Drug–induced ANCA–positive vasculitis from minocycline and hydralazine can be ruled out by taking a detailed drug history .
What is the treatment for levamisole-adulterated cocaine vasculopathy?
The main treatments for levamisole-adulterated cocaine vasculopathy are to withdraw the drug and to provide supportive care. Most retiform purpura resolves within 2–3 weeks without specific treatment after avoiding levamisole-adulterated cocaine . However, if there is full–thickness skin necrosis (grade IIb to III), surgical debridement, grafting and specialist wound management is needed [7,11].
The role of systemic corticosteroids is controversial, although they are often used in patients with progressive skin disease or systemic involvement [1,4,9]. Targeted antibiotics are indicated for patients with fever or clinical evidence of bacterial skin infection after ruptured bullae . Granulocyte macrophage stimulating factors have been used for severe neutropenia. Patients with pulmonary haemorrhage may be treated with plasmapheresis and immunosuppression .
What is the outcome for levamisole-adulterated cocaine vasculopathy?
The majority of patients have full resolution of symptoms and signs after withdrawal from levamisole–adulterated cocaine.
Symptoms may recur with continued use of cocaine, and can be more extensive [4,6,11].
Bacterial wound infection, surgical debridement and complex wound care may be followed by scarring and contractures. There has been one case report of a wound necessitating amputation . Untreated renal impairment may lead to chronic renal disease .