Vasculopathy for cocaine adulterated with levamisole

What is levamisole?

Levamisole is an anthelmintic drug that is 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 retiformis purple 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 immunomodulatory agent for the treatment of lichen planus, pediatric nephrotic syndrome and rheumatoid arthritis after its approval by the United States Food and Drug Administration in 1991.

What is cocaine adulterated with levamisole? vasculopathy?

Cutaneous Vasculopathy associated with cocaine adulterated (contaminated) with levamisole is an emerging syndrome characterized by retiform purpura around the ears, the presence of anti-neutrophils cytoplasmic autoantibody (HAUNCH) and leukopenia [3,4].

Levamisole-adulterated cocaine vasculopathy was first described in the late 2000s after an increase in levamisole cocaine cordon.

Who gets levamisole-adulterated cocaine vasculopathy?

In 2010, 80% from cocaine seized by US authorities was levamisole-adulterated [2,5]. Levamisole-adulterated cocaine vasculopathy is reported exclusively in cocaine users, most often with chronic use and in those who smoke and snort contaminated cocaine [6,7]. It can also occur when cocaine is injected.

The average age of patients at presentation is 44 years. [1]. Cocaine vasculopathy adulterated with levamisole is more predominant in women, in a ratio of 1: 3 [1]. Human class 1 major histocompatibility complex (MHC) carriers White blood cell antigen (HLA) –B27 are at risk of developing levamisole-related agranulocytosis [5].

What Causes Levamisole-Adulterated Cocaine Vasculopathy?

The exact cause of levamisole-adulterated cocaine vasculopathy is unknown. It is associated with immunity dysfunction.

• the inflammation small and medium size blood vessels in the skin, it has a different serological profile from cocaine-related pure vasculopathy, and is probably due to the levamisole component [1,2,7].
• One of the three breakdown products of levamisole, known as 6-phenyl-2,3-dihydroimidazo (2,1b) -thiazole, has lymphocyte-stimulants, which could play a role in Pathogenesis [8].
• Levamisole can cause the production of extracellular neutrophil traps (NETs) that are released from neutrophils during cell death by a variety of stimuli. NETs activate the adaptive immune response, leading to the production of ANCA [5].

What are the clinical features of levamisole-adulterated cocaine vasculopathy?

Skin characteristics

Retiform purple is tender dark purple papules, with a nopallor center and a erythematousirregular edge [9]. They appear about 4 days after using levamisole-adulterated cocaine. Papules tend to be bilateral and symmetrically distributed. Affected sites may include:

• Ears (lobe or outer edge)
• Tip of the nose
• Malar cheek region
• Trunk
• Proximal extremities
• Buttocks and lower extremities [9–11].

Systemic features

Systemic features of levamisole-adulterated cocaine vasculopathy may include:

• Arthralgia [9]
• Rhinorrhea (runny nose)
• Sinusitis [9].

Manifestations of the upper respiratory tract include:

• Mouth ulcers and nasopharyngeal ulcers

• Oral yeast infection
• Pharyngitis
• Odynophagia (pain when swallowing).

These are related to a low white blood cell count (neutropenia) [7].

Constitutional symptoms include [9]:

• Fever
• Night sweats
• Weightloss
• Myalgia.

What are the complications of levamisole-adulterated cocaine vasculopathy?

Skin complications

• Blisters, which can lead to necrosis [7,11]
• Ears autoamputation and digits [1]
• Secondary bacterial skin infection [1,10]
• Scars at the sites of confluent purple, bullas and necrosis; If necrosis is extensive, surgical amputation may be necessary [11].

Systemic complications

• Neutropenia and agranulocytosis have been observed, which can lead to systemic bacterial infections or fungal infections. [6]
• Acute renal failure and cases of biopsyProven pauci-immune glomerulonephritis have been recorded. One case progressed to chronic renal failure [5].
• At least three cases of pulmonary hypertension has been reported in patients with levamisole-adulterated cocaine vasculopathy [4].
• A case of pulmonary hemorrhage It has been reported [4].

• There has been a case report of concurrent Cocaine-induced and levamisole-adulterated cocaine vasculopathy middle line destructive injury (CIMDL) [7].

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.

Serum tests

Serology is positive with high titers of perinuclear ANCA (p-ANCA, 84%), antinuclear, lupus anticoagulant, human neutrophil elastase, anti-myeloperoxidase (100%), anti-proteinase 3 (50%) and anti-phospholipid antibodies (63%) [8,10].

• Leukopenia occurs in 28% of patients. [12].
• Neutropenia (<1.5 × 10^{9 9}granulocytes/ L) and agranulocytosis (<0.5 x 10^{9 9} granulocytes / L) occur in 2.5 to 13% of patients [11].

Urine tests

To ensure positive urine toxicology, a urine sample should be collected within 4 days of the last cocaine use. [7].

• Levamisole in urine is detected by gas chromatography with mass spectrometry and should 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, hematuria, and cellular molds [2.12].

Histology recommendations

Skin biopsy should be performed to exclude other causes of vasculitis, but it does not involve the direct consumption of cocaine adulterated with levamisole [6].

There are two classic features seen in levamisole-adulterated cocaine vasculopathy:

• Leukocytoclastic small vessel vasculitis [1]
• Multiple fibrin thrombi within small vessels on the surface and deep dermis [1].

Both findings are generally present, but fibrin thrombi are the most consistent feature [3]. Direct immunofluorescence is unspecific.May show immunoglobulin (Ig) A, IgM, C3 and intravascular fibrin [10].

Classification of severity of disease

A classification system based on cutaneous manifestations has been proposed for the severity of the disease, stratifying the disease into mild, moderate and severe. [eleven]. The authors noted that, in stage 3 disease, withdrawal of adulterated levamisole-cocaine alone will not result in skin resolution [11].

Stage 1 (mild)

• Mild purpura without necrosis.
• Discontinuation of LAC, spontaneous healing expected

Stage 2 (moderate)

• Purple Patches /plates without ulceration
• Discontinuation of LAC, spontaneous healing expected

Stage 3 (severe)

• Confluent purpura with or without necrosis
• Discontinuation of ALC, hospital admission with debridement and guaranteed graft after observing for 72 hours.
• Withdrawal of cocaine adulterated with levamisole alone will not result in skin resolution.

NOTE: early debridement was associated with the development of new lesions probably due to pathergy phenomenon.

Which is the differential diagnosis for levamisole-adulterated cocaine vasculopathy?

The use of cocaine adulterated with levamisole can be confused with other forms of cutaneous vasculitis; these include:

• ANCA-positive associated vasculitis such as granulomatosis with polyangiitis and microscopic polyangiitis

• Small vasculitis and medium size vasculitis.

• Antiphospholipid syndrome

• Cryoglobulinemia.

Anti-phospholipid antibodies, lupus anticoagulant, high-titer ANCA and multiple constituents of neutrophilic granules Helps differentiate levamisole-adulterated cocaine vasculopathy from other ANCA-positive vasculitis.

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)
• Staphylococci bacteremia (the most common cause of septicemia)
• Angioinvader deep fungal infections
• Septic plungers

For patients undergoing anticoagulant therapy, warfarin-induced skin necrosis, disseminated intravascular coagulation or heparin-induced thrombocytopenia should be considered [3,7,8]. ANCA-positive vasculitis induced by minocycline and hydralazine drugs can be ruled out by taking a detailed history of the drugs. [8].

What is the treatment for levamisole-adulterated cocaine vasculopathy?

The main treatments for levamisole-adulterated cocaine vasculopathy are withdrawing the drug and providing supportive care. Most retiform purpura resolves in 2 to 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 specialized wound management are required [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 bullae rupture [6]. Granulocytes macrophage Stimulating factors have been used for severe neutropenia. Patients with pulmonary hemorrhage can be treated with plasmapheresis and immunosuppression. [5].

What is the outcome of levamisole-adulterated cocaine vasculopathy?

Most patients have complete resolution of symptoms and signs after withdrawal of levamisole-adulterated cocaine.

Symptoms can recur with continued cocaine use and can be more extensive [4,6,11].

Bacterial wound infection, surgical debridement, and complex wound care can be followed by scars and scars. contractures. There has been a case report of a wound requiring amputation [11]. Untreated kidney failure can lead to chronic kidney disease [5].