Levamisole-induced leukocytoclastic vasculitis and neutropenia in a patient with cocaine use: An extensive case with necrosis of skin, soft tissue, and cartilage

According to July 2009 estimates, 69% of the cocaine seized by the US Drug Enforcement Administration (DEA) is adulterated with levamisole[1, 2]. Levamisole is a veterinary antihelminthic agent that has recently been linked to vasculitis and neutropenia in people with cocaine use[3, 4]. We describe a cocaine user with levamisole-induced necrosis of the skin, soft tissue, and cartilage resulting in nasal amputation, earlobe necrosis, and bilateral above-knee amputation (AKA). To the best of our knowledge, this is only the second case of levamisole-induced vasculitis requiring above-knee amputation to be reported in the English language literature, and it is also one of the first reported cases with laboratory confirmation of levamisole exposure.

Levamisole is a veterinary antihelminthic agent currently used to treat worm infestations in cattle, sheep, and pigs[5]. In the past, it was used in humans to treat various autoimmune disorders and cancers because of its immunomodulatory properties[5]. Levamisole-induced vasculitis (LIV) was first reported in a rheumatoid arthritis patient in 1978[6]. Since 2009, levamisole has also been linked to cutaneous vasculitis in people who use cocaine.

To the best of our best knowledge, 32 cases of LIV in patients with cocaine use have been reported to date[3, 4, 7‐22]. Clinical features, laboratory results, skin biopsy findings, and the treatment of these patients are summarized in Tables1,2 and3. Of the 32 patients described, only eight had levamisole exposure confirmed by urinalysis or GCMS, although other authors speculated on this link based on the presence of levamisole in approximately 69% of the cocaine entering the United States. Among all the reported cases, only one (published twice by different authors, i.e., Ching et al.[15] and Mouzakis et al.[16]) had extensive necrosis requiring AKA. The patient was a 54-year-old man positive for p-ANCA who developed fever, agranulocytosis, and extensive skin necrosis following heavy intranasal cocaine use. Necrosis was present on more than 50% of his total body surface area, requiring thorough wound debridement, skin grafting, and left-sided AKA. Unlike our patient, AKA in this case was unilateral, and levamisole exposure was not confirmed by GCMS since the patient presented late after the likely exposure. The authors speculated that levamisole exposure was probable based on the patient’s clinical presentation and history of cocaine use. Our patient represents the most extensive confirmed case of LIV with involvement of 35% of her total body surface area.

Levamisole was an FDA-approved drug but was withdrawn for use in humans in the USA in 1999 due to reports of serious adverse effects such as agranulocytosis, thrombocytopenia, arthritis, and LIV[23‐26]. However, it is still available for animal use in the United States, Canada, and South America[26]. In the presence of alternative and more efficacious veterinary antihelminthics, such as ivermectin[27, 28], the reasons for continued availability of levamisole for animal use are poorly understood, especially in light of the emerging data on the potential dangers of its addition to cocaine.

The practice of adulterating cocaine with levamisole has increased significantly in recent years[26, 29]. Several theories exist to explain the reasons for adulterating cocaine with levamisole. One explanation may be levamisole’s ability to potentiate the psychotropic effects of cocaine[26]. Stimulant effects of cocaine are mediated by the blockage of presynaptic reuptake pumps for the monoamine neurotransmitters dopamine, norepinephrine, and serotonin in the central and peripheral nervous systems leading to their enhanced activity[30, 31]. Animal data suggest that levamisole may have an inhibitory action on monoamine oxidase and catechol-O-methyltransferase, the enzymes that metabolize catecholamine neurotransmitters[26]. Therefore, levamisole may potentially inhibit the degradation of these stimulatory neurotransmitters, prolonging the duration of their action and adding to the reuptake-inhibition effect of cocaine. Clinically, this may result in enhanced psychotropic effects[26]. Antihelminthic properties of levamisole are due to its species-specific agonistic action at nicotinic acetylcholine receptors of the muscle cells of nematodes[32]. Cocaine may also act on the nicotinic acetylcholine receptors of humans, resulting in increased dopaminergic reuptake inhibition and glutamatergic activity[33]. Although unlikely due to species-specific action of levamisole, it is theoretically possible that cocaine and levamisole may have a synergistic action at nicotinic acetylcholine receptors resulting in increased nicotinic and dopaminergic effects[26]. Also, studies in horses have suggested that levamisole may get metabolized to aminorex, an amphetamine derivative with stimulant effects similar to cocaine and amphetamine[34]. Other possible explanation for using levamisole as a cocaine adulterant may be its use as a “marker” or “signature” compound by manufacturers to trace its market distribution[26]. Some media reports suggest that levamisole is used as a cutting agent for cocaine because it adds bulk and weight to powdered crack cocaine while retaining the appearance and look of pure cocaine, and it also has the ability to pass cocaine purity tests used by drug dealers. Levamisole-induced cutaneous vasculitis has been reported both with smoked crack cocaine[17] and inhaled powdered cocaine[21], indicating that both are adulterated with levamisole.

In addition to levamisole, other commonly used cocaine adulterants include local anesthetics, sugars, stimulants (such as caffeine, ephedrine, phenylpropanolamine, and amphetamines); toxins (such as quinine and strychnine); and inert compounds[35]. Among these cocaine adulterants, only stimulants have been associated with vasculitis upon chronic use. Unlike LIV, the vasculitis associated with chronic stimulant use is usually cerebral or systemic in distribution[35].

As LIV is usually associated with the generation of autoantibodies such as p-ANCA, ANA, and lupus anticoagulant, it may be difficult to differentiate it from autoimmune disorders such as Wegener’s granulomatosis and other small-vessel vasculitides. The exact pathogenic mechanisms responsible for the formation of these autoantibodies remain elusive. Recent reports have suggested that, due to its ability to act as a hapten, levamisole may cause increased formation of antibodies to various antigens and therefore lead to an immune response involving the opsonization and eventual destruction of the leukocytes[33].

Before the recognition of levamisole as an adulterant in the cocaine supply, cocaine alone was associated with an p-ANCA-positive pseudovasculitis in some previous reports[36]. Although clinical presentation and laboratory findings of pseudovasculitis may be similar to true vasculitis, biopsy specimens in pseudovasculitis patients do not reveal the typical histopathologic findings seen in patients with true vasculitis[36]. Moreover, there is a possibility that these cocaine-related pseudovasculitis cases were actually caused by unrecognized contamination with levamisole.

Adulteration of the majority of the cocaine supply entering United States with levamisole is concerning, especially in view of the high frequency of cocaine use in this country. According to the August 2005 National Survey on Drug Use and Health (NSDUH) Report, more than 5.9 million (2.5%) persons aged 12 years or older used cocaine in 2002-2003[37].

Based on published reports, Levamisole-induced cutaneous vasculitis in cocaine users is more commonly seen in women[3]. Clinical features commonly include a tender purpuric rash in a retiform/reticular distribution with or without necrosis[3]. In addition to leukopenia and neutropenia, laboratory results are usually positive for different types of auto-antibodies such as c-ANCA, p-ANCA, ANA, and lupus anticoagulant[3]. Recurrence or exacerbation of skin lesions with cocaine use have been reported in some cases. Skin biopsy shows either a mixed pattern of leukocytoclastic and thrombotic vasculitis or an isolated thrombotic vasculopathy[3].

Cessation of cocaine use and supportive care of LIV-related skin lesions lead to resolution of symptoms in most of the cases. Steroids have been used in a significant number of previously reported cases with a variable response. The recurrent lesions in our patient improved significantly after intravenous methylprednisolone. However, due to the risk of increased susceptibility to superimposed infections, steroid use should be limited to more severe cases that fail to respond to supportive care. Patients should be educated about the possible adverse effects of future cocaine use. Extensive skin involvement and necrosis may need surgical debridement and skin grafting. As happened in our patient, in extreme cases that involve extensive necrosis, amputation may be required to contain necrosis and infection.

Adulteration of cocaine with levamisole is widely prevalent in United States. Levamisole may cause cutaneous vasculitis and neutropenia in people with cocaine use. History of cocaine use should be explored in patients presenting with a rash and neutropenia, and testing for levamisole exposure should be performed in selected patients. In cases with extensive involvement, this condition may lead to disfigurement by causing necrosis of skin, soft tissue, and cartilage.