Introduction - levamisole Introduction - levamisole-adulterated cocaine vasculopathy Demographics Causes Clinical features Complications Diagnosis Differential diagnoses Treatment Outcome
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.
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.
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 [1]. Levamisole-adulterated cocaine vasculopathy is more prevalent in women, at a ratio of 1:3 [1]. Patients carrying the major histocompatibility complex (MHC) class 1 human leukocyte antigen (HLA)–B27 are at risk of developing levamisole related agranulocytosis [5].
The exact cause of levamisole-adulterated cocaine vasculopathy is unknown. It is associated with immune dysfunction.
Retiform purpura are tender dusky purple papules, with a non-blanching centre and an erythematous, irregular border [9]. They appear about 4 days after using levamisole-adulterated cocaine. The papules tend to be bilateral and symmetrically distributed. Affected sites may include:
Systemic features of levamisole-adulterated cocaine vasculopathy may include:
Upper respiratory tract manifestations include:
These are related to low white blood cell count (neutropenia) [7].
Constitutional symptoms include [9]:
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].
To ensure urine toxicology is positive, a sample of urine must be collected within 4 days of the last use of cocaine [7].
Skin biopsy should be performed to exclude other causes of vasculitis, but it does not implicate levamisole-adulterated cocaine use directly [6].
There are two classic features seen in levamisole-adulterated cocaine vasculopathy:
Both findings are usually present, but fibrin thrombi are the more consistent feature [3]. Direct immunofluorescence is nonspecific. It can show immunoglobulin (Ig) A, IgM, C3 and intravascular fibrin [10].
A grading system based on cutaneous manifestations for disease severity has been proposed, stratifying disease into mild, moderate and severe [11]. The authors noted that, in stage 3 disease, withdrawal of levamisole–adulterated cocaine alone will not result in cutaneous resolution [11].
NOTE: early debridement was associated with the development of new lesions likely due to pathergy phenomenon.
Levamisole-adulterated cocaine use can be confused with other forms of cutaneous vasculitis; these include:
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:
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 [8].
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 [3]. 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 [6]. Granulocyte macrophage stimulating factors have been used for severe neutropenia. Patients with pulmonary haemorrhage may be treated with plasmapheresis and immunosuppression [5].
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 [11]. Untreated renal impairment may lead to chronic renal disease [5].
