2020-10-26 oliver 11 Comments UPDATE: I originally posted this as an unknown, but have become convinced that Dr. Stewart’s diagnosis of levamisole vasculopathy is correct. This decedent had similar lesions on his nose and cheeks, which is consistent with this diagnosis, and has a history of crack/cocaine use. For nice reviews, see here and here. Levamisole Induced Necrosis Syndrome (LINES) is a complication of adulterated cocaine recognized in 2011, caused by the use of levamisole as a cutting agent for cocaine. Spontaneous bruising of the earlobes is considered characteristic of this condition, but lesions can present anywhere on the body. Best Way To Make Crack “In a large metal spoon, combine 1 gram of cocaine and ½ gram of baking soda. Carefully fill the spoon with water to the ¾ mark. Place the spoon with all three ingredients over medium high to high heat until all of the baking soda has finished bubbling out. Levamisole is a veterinary drug used to deworm animals now being used as a filler in cocaine. Nov 09, 2020 The U.S. Substance Abuse and Mental Health Services Administration (SAMHSA) issued a warning to substance abuse treatment centers, medical professionals and other public health authorities about the dangers of cocaine laced with levamisole, a drug used to prevent parasites in cattle, sheep and swine.

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Diagnosis Synopsis

Cocaine Levamisole Toxicity : Cocaine contaminated with levamisole has been detected in the United States since 2003, and the incidence of toxicity caused by this contamination has been increasing rapidly since 2008. Use of cocaine that has been adulterated with levamisole can lead to a constellation of symptoms including agranulocytosis, neutropenia, and a vasculitis-like purpuric tender skin eruption. The most common sites of purpura are the external ears and cheeks. The purpura is generally followed by skin necrosis, but resolves several weeks after cessation of cocaine use. Recurrent use of contaminated cocaine generally results in recurrent skin eruptions.

Concomitant symptoms of arthralgias, fever, and mouth pain have been reported.
The CDC estimates that approximately 70% of cocaine in the United States may be contaminated with levamisole. Toxicity induced by levamisole seems to affect all ages and both genders equally depending on cocaine use. The cocaine can be either smoked as crack cocaine or snorted. Some analyses have revealed up to 10% contamination of individual cocaine products.
Because levamisole is difficult to test for and because other treatable causes of vasculitis may be present, levamisole-induced toxicity is a diagnosis of exclusion. Several published cases have had concurrent or preceding medical histories that involve both chronic and acute infections as well as signs of chronic autoimmune disease. Other cases have had absolutely no preceding medical history.
Since neutropenia is a common presenting sign of this toxicity, bacterial or fungal infections may be presenting features of levamisole toxicity.

Look For

Somewhat tender purpuric macules and papules on the helix of the ear or the cheeks. Retiform or stellate purpura on the trunk and extremities that can progress to bullae. Very early, the purpura may be preceded by erythematous macules. Progression of the purpura to necrosis and crusting eschars is common before resolution.
Dark Skin Patient Considerations
In dark-skinned individuals, the rash may present with deep red to brown or purple macules and papules. Purpura is difficult to detect in extremely dark skin.

Diagnostic Pearls

Neutropenia is a common laboratory finding. The combination of neutropenia in a patient with purpura of the ears and a urine toxicology screen positive for cocaine should suggest levamisole-induced vasculitis. Levamisole testing of serum or urine is difficult and unreliable.
Multiple autoimmune serological markers can be positive including anti-dsDNA, ANCAs, platelet factor IV antibody, lupus anticoagulant, Russell viper venom time, elevated PTT, and anticardiolipin IgM. Careful consultation with rheumatology to consider autoimmune diseases is recommended.

Differential Diagnosis & Pitfalls

The differential diagnosis for cocaine levamisole toxicity includes many of the same diagnoses as for leukocytoclastic vasculitis (LCV) or drug toxicities. Secondary causes of LCV such as infection, medication reactions, neoplasms, and autoimmune connective tissue disorders should be sought out.

• Cryoglobulinemia – check for serum IgM and IgG cryoglobulins, HCV infection.
• Cryofibrinogenemia
• Bacterial sepsis
• Coumadin necrosis
• Heparin necrosis
• Purpura fulminans
• Acute meningococcemia – the patient is usually systemically ill, but since cocaine use may complicate the neurologic exam, this diagnosis should be considered carefully.
• Calciphylaxis
• Vasculitis secondary to viral infections such as hepatitis A, B, C, VZV, parvovirus B19, and CMV, or to medications.
• Arthropod bites
• Erythema multiforme minor (EM) – characteristic findings on histology will assist in differentiating EM from LCV. Systemic involvement is rare.
• Toxic epidermal necrolysis (TEN) – usually larger areas of skin are involved with more skin pain and resulting bullae.
• Frostbite or chilblains (perniosis) – history of recent cold exposure.
• Microscopic polyangiitis is ANCA positive and has palpable purpura and constitutional symptoms; look for evidence of pulmonary and renal involvement.
• Wegener's granulomatosis is ANCA positive and has necrotizing granulomatous inflammation of the upper and lower respiratory tracts, glomerulonephritis.
• Churg-Strauss syndrome is ANCA positive and is associated with eosinophilia and asthma.
• Polyarteritis nodosa – medium vessel vasculitis with subcutaneous nodules, livedo reticularis, ulcers, and gangrene as cutaneous manifestations.
• Immune thrombocytopenic purpura – look for isolated thrombocytopenia.

Sometimes non-vasculitic purpura on the lower extremities may be palpable such as those seen in the following:

• Over-anticoagulation with Coumadin (warfarin) or heparin
• Early disseminated intravascular coagulation

Best Tests

Cocaine levamisole toxicity is a diagnosis of exclusion and depends heavily on the history. Although very suggestive, the use of cocaine before a characteristic purpuric eruption does not necessarily implicate this drug or contamination with levamisole. It is critical to identify other treatable causes of vasculitis such as infection or autoimmune disease. It is also important to evaluate and identify any internal organ involvement.
A skin biopsy will be helpful to rule out other diseases but will not implicate cocaine or levamisole directly. Fibrin thrombi are commonly seen in the vessels, but all features of leukocytoclastic vasculitis may not be present.
Laboratory studies:

• Urine toxicology to detect cocaine use
• Liver function tests
• CBC with differential (neutropenia is a common associated finding; also look for the presence of leukocytosis, eosinophilia, and atypical lymphocytes to indicate ongoing infection or leukemia)
• Urinalysis and renal function tests

Lumbar puncture or imaging studies can be ordered to rule out other causes of vasculitis or altered mental status if localizing symptoms are present.
A skin biopsy will likely be helpful, but this diagnosis depends on ruling out other causes of vasculitis.

Management Pearls

Consultations may be needed with dermatology, critical care, infectious disease, and rheumatology. Depending on the level of cocaine abuse or the use of other addictive drugs, psychiatry may need to be consulted during withdrawal.
Elevated serological markers tend to resolve after 2-10 months.
When patients are severely neutropenic, care should be taken to monitor for concurrent bacterial and fungal infections.

Therapy

Use of contaminated cocaine must be stopped immediately. Management is generally supportive. Many patients will recover spontaneously, although sometimes slowly. Optimize supportive care for any specific complications or wound care.
Authors
Art Papier MD, Noah Craft MD

• Dosage

Usual Adult Dose for Malignant Disease

50 mg orally every 8 hours for 3 days (starting 7-30 days post-surgery). May be given as maintenance therapy for 3 days at 2 week intervals for 1 year.

Dose Adjustments

Levamisole Crack Cocaine

The dosage may depend upon the specific indication for use. Reference to specific protocols is recommended.

Precautions

If the WBC count is 2,500-3,500/mm³, defer the fluorouracil dose until the WBC count is > 3,500/mm³. If the WBC count is < 2,500/mm³, defer the fluorouracil dose until the WBC count is > 3,500/mm³ and resume the fluorouracil dose reduced by 20%. If the WBC count remains < 2,500/mm³ for over 10 days, despite deferring fluorouracil, discontinue administration of levamisole. Both drugs should be deferred when the platelet count is < 100,000/mm³.

Other Comments

Levamisole is indicated as adjuvant treatment in combination with fluorouracil after surgical resection for Duke's stage C colon cancer. On the first day of combination therapy, a CBC with differential and platelets, serum electrolytes, and liver function tests are recommended. Thereafter, a weekly CBC with differential and platelets prior to each treatment with fluorouracil is recommended. Serum electrolytes and liver function tests are recommended every 3 months for a total of 1 year. The patient should be informed that if flu-like symptoms, malaise, severe stomatitis and/or diarrhea occur, the physician should be notified immediately.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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