Levamisole-induced Necrosis Syndrome: Presentation and Management

Levamisole is an antihelminthic drug with immunomodulatory properties. Recent estimates suggest the majority of the cocaine in the United States is adulterated with levamisole. Levamisole-induced necrosis syndrome (LINES) is characterized by vasculitis, neutropenia, and purpura that progresses to skin necrosis.Diagnosis relies on physical examination findings and history of previous cocaine use. The purpose of this case series is to describe the pathophysiology, diagnosis, and management of LINES. The authors’ institutional database was reviewed from 2008 to 2015, and they found 3 patients with LINES. Subsequent management and outcomes data are discussed. Patients had a variety of outcomes ranging from local wound care to necrosis and amputation of phalanges. Patients with LINES can have a wide variety of outcomes; thus, this syndrome must be aggressively managed. Psychotherapy should also be utilized to help patients with further cocaine use. Levamisole-induced necrosis syndrome incidence is expected to increase, and all providers should be aware of this patient population.

Cocaine is a recreational stimulant used by approximately 1.8% (5.65 million) of the US population in 2012.¹ Its effects are mediated by the inhibition of dopamine reuptake and lead to feelings of self-assuredness and psychic contentment, which can result in a high rate of dependence. According to the US Drug Enforcement Administration (DEA), 69% of the cocaine supply in the United States contains levamisole, a drug that is currently used to treat parasitic infections in animals, and this percentage is increasing.² Formerly used to treat pediatric nephrotic syndrome, rheumatoid arthritis, and colon cancer in conjunction with 5-fluorouracil, levamisole is no longer on the market due to its association with agranulocytosis and cutaneous vasculitis.^3,4 Levamisole is used as an adulterant to “cut” cocaine as it is widely available and can be reduced to a very fine powder. The increasing prevalence of levamisole in cocaine over the last decade has led to an exponential increase in the number of case reports of levamisole-induced necrosis syndrome (LINES) in cocaine users, some of which require extensive surgical debridement and skin grafting. Levamisole-induced necrosis syndrome can result in painful, retiform, purpuric lesions that can progress to full-thickness skin necrosis. Herein the authors present a series of 3 patients and their 13 admissions for levamisole-induced vasculitis as well as the subsequent surgical and wound management.

All patients who presented for LINES to the Department of Trauma and Burn, John H. Stroger, Jr., Hospital of Cook County (Chicago, IL) were identified, with the first presentation starting in 2009. The average patient’s age was 29.3 years, and all patients were female. Table 1 contains patient demographics and case specifics. Table 2 summarizes individual admissions. All patients were evaluated and managed by the burn surgery team, with additional consults to plastic surgery as indicated.  

Case 1. A 25-year-old woman with no medical history presented with an altered mental status and 15.5% total body surface area (TBSA) irregular black lesions involving her bilateral lower extremities, left ear, and left cheek. She was initially admitted to the Medical Intensive Care Unit over concerns of meningococcemia that was later ruled out. Her wounds were treated with a petrolatum gauze dressing impregnated with 3% bismuth tribromophenate (Xeroform Petrolatum Wound Dressing; DeRoyal, Powell, TN), and she was discharged home. Seventeen days following discharge, she again presented to the Emergency Department after using cocaine from the same supplier with progression of purpuric lesions to full-thickness necrosis. She underwent operative debridement of her lower extremity lesions but did not ultimately require skin grafting. She was discharged home with her wounds healing by secondary intention. 

Case 2. A 26-year-old woman with systemic lupus erythematosus (SLE) on chronic prednisone therapy presented as a burn surgery consult with painful, red, reticulated plaques with central necrosis over her bilateral lower extremities, ears, and chest. Total involvement was 10% TBSA (Figure 1). Upon further review of her chart, she was admitted 2 previous times with similar skin lesions but was diagnosed with a SLE flare. Previous skin biopsies were reviewed, with the patient’s perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) and antinuclear antibodies (ANA) testing positive and pathology showing perivascular lymphocytic infiltrate with thrombi in small vasculatures. The diagnosis of LINES was made based on her history of recent cocaine use and concurrent skin lesions. Her wounds were dressed with a petrolatum gauze dressing impregnated with 3% bismuth tribromophenate, and she continued her prednisone therapy. Despite counselling, the patient continued to abuse cocaine and would later require 7 additional hospital admissions over the subsequent 3 years due to ongoing exposure to levamisole and recurrent LINES. 

Case 3. A 35-year-old woman with history of sarcoidosis  and pyoderma gangrenosum of the lower extremities presented with 26% TBSA purpura involving bilateral lower extremities, both hands, face, and oral mucosa 7 days after administering cocaine nasally by inhalation (Figure 2). She presented with acute kidney injury (AKI) and a creatinine of 2.5 mg/dL. She required oxygen supplementation due to the extensive involvement of her facial lesions and was unable to eat due to pain. 

After progression to full-thickness wounds over the next 14 hospital days, she underwent tracheostomy, percutaneous gastrostomy feeding tube placement, amputation of left fingers 2 through 5 and right fingers 4 and 5, and debridement of bilateral lower extremities. The plastic surgery service debrided the central portion of her nose, lips, and mucosal lining of her nose. She later underwent 1 revision of her finger amputations and repeat debridement of her lower extremity wounds. On hospital day 22, she underwent excisional split-thickness skin grafting of her bilateral lower extremities with a 2:1 meshed graft and 1:1 meshed graft of her left hand. Three months after discharge, the plastic surgery service performed contracture release and full-thickness skin grafting of her perioral, nasal, and orbicularis tissues. 

All patients were cocaine positive on urine toxicology. The most common symptoms of pain, fevers, and myalgia were seen in all patients in at least 1 of their admissions. Laboratory testing revealed elevated p-ANCA (2/3 patients), agranulocytosis (1/3), and AKI (1/3). Of the 3 patients, 2 required operative debridement.

The DEA first documented the presence of levamisole in cocaine shipments in 2003.⁵ By 2010, the Colorado Department of Public Health and Environment found that 203 out of 300 urine samples that had tested positive for cocaine also contained levamisole.⁶ Likely to be originating from Colombia, the distribution is global; levamisole has been found in a smaller but increasing number of samples in Europe.^1,7

Theories surrounding the emergence of levamisole in the drug supply are two-fold. One, its similar white, powdered properties can increase the volume of drugs sold. Due to several geopolitical forces, including cartel wars in Mexico, increased border seizures, and decreased coca bush growth, pure cocaine availability has decreased since 2006.¹ Two, its metabolite aminorex, a stimulant with a longer half-life than cocaine, may prolong the duration of euphoria.⁸

The characteristic cutaneous involvement is painful, retiform purpuric lesions with occasional bullae that can progress to full-thickness dermal sloughing. Histological analysis shows small vessel thrombosis and vasculitis. The formation of autoantibodies may be responsible for the vasculitis, as demonstrated by its association with p-
ANCA, cytoplasmic-ANCA, and antihuman elastase antibody. In a review⁹ of levamisole-induced vasculopathy, 88% of patients were p-ANCA positive. Of the 11 patients tested for antihuman elastase antibody, 100% were positive.⁹ The combination of vasculitis and cocaine-induced vasoconstriction may place the small vessels of the nose, face, and, most notably, ears at increased risk of necrosis. All 3 of the patients included in this case series had facial involvement. As indicated in the aforementioned review, ⁹ the most common involvement was the lower extremities, with 84% involvement, followed by the ears and face. 

The cases reported in the literature demonstrate a wide range in skin depth and skin extent. To the best of the authors’ knowledge, the first reported case of full-thickness wounds requiring skin grafting was a 54-year-old man in Louisville, Kentucky, in 2012. Skin grafting occurred 7 days post admission with progression of the lesions into eschar.¹⁰ The most extensive case of levamisole-induced vasculitis was 52% TBSA; this patient required multiple skin grafts and eventually an above-the-knee amputation.¹¹  

From the authors’ experience, the development of purpuric lesions to full-thickness necrosis is unpredictable. In case 3, this progression occurred over a 14-day period, following nasal ingestion and inhalation of crack cocaine. She required several debridements and, to the best of the authors’ knowledge, this is the first reported case of tracheostomy and feeding tube placement for LINES. However, case 1 initially improved with cessation of cocaine over the course of 5 days, only to present 3 weeks later with worsening disease following ongoing cocaine abuse. 

It is unknown if disease progression is due to the amount of levamisole ingested, chronicity of exposure, synergistic effects of cocaine-induced vasoconstriction and levamisole thrombosis, or interaction with human leukocyte antigen B27.³ Four million US citizens are exposed to levamisole yearly, and the number of patients who present with LINES is substantially lower. Furthermore, the authors’ experience shows a high recurrence following re-exposure, and a potential cumulative effect on ingestion. This may be higher than the cited 27% recurrence in the literature, but it is difficult to ascertain the number of drug ingestions that did not lead to hospital admission.³ 

Skin necrosis is not the only manifestation of levamisole toxicity. In a series of 30 patients at Massachusetts General Hospital,¹² the majority of patients presented with arthralgia, with more than a quarter exhibiting leukopenia on admission. Less frequently, patients can present with pulmonary and renal manifestations.¹² 

The combination of vague systemic symptoms with cutaneous involvement can make accurate diagnosis of this rare syndrome a challenge; this is exemplified by the authors’ experience with patients who have co-
existing autoimmune diseases and a subsequent delay in diagnosis. This is also described in the literature, as one case series had 5 of 6 patients initially misdiagnosed with autoimmune vasculitis.¹³ Furthermore, infection (meningococcemia), drugs (warfarin-induced skin necrosis, unadulterated cocaine), and autoimmune diseases (cryoglobulinemia) can cause retiform purpuric lesions.¹⁰

Due to the extensive differential, Lee et al¹⁴ provided a comprehensive diagnostic algorithm if LINES is suspected, and it first starts with urine toxicology for cocaine. This should occur within 48 hours by gas chromatography due to the short 5.6-hour half-life of levamisole.¹⁵
If urine is positive for cocaine, a complete blood count with differential will assess for agranulocytosis. If the patient is neutropenic, testing for ANCA, cryoglobulins, and antiphospholipid antibodies is recommended.¹⁴ However, due to the combination of the extremely short half-life and the difficulty of obtaining gas chromatography, many providers must use clinical judgment in combination with a history of recent cocaine use.  

Following cessation of cocaine, medical immunosuppression and even plasmapheresis have been suggested but unproven treatments of LINES.¹⁶ Wound care management and debridement follows classic burn surgery principles: debridement to healthy tissue and subsequent reconstruction. Miner et al¹⁷ suggest a benefit to early excision and grafting similar to full-thickness burns. The present authors also recommend an early excision and grafting approach with timing based on clinical demarcation of wounds in order to limit the delay in definitive treatment. The experience of the authors herein corroborates other reports, with successful excision on hospital day 14 and subsequent grafting without any ensuing graft loss.¹⁷ This case series highlights the range of treatment options for LINES: wound care with medical immunosuppression, surgical excision alone, and early excision and grafting. 

Levamisole-induced necrosis syndrome represents a major shift in the illicit supply of cocaine in the United States and represents a growing public health concern. Due to the increasing use of levamisole as an adulterant, the authors also expect the incidence of LINES to increase on a national level. Knowledge of this rare but increasingly common disease process helps identify patients earlier and helps avoid delayed diagnosis due to broad differentials. When identified, the authors recommend early burn surgery consultation and intensive wound care management with moist semi-occlusive dressings and debridement and grafting when indicated. Operative intervention should occur for wound sepsis or full-thickness necrosis. There are positive outcomes for patients with LINES, but the favorable outcome is directly related to the areas involved and the degree of necrosis. Diagnosis of LINES requires a high index of suspicion, and this syndrome should be discussed with all patients who abuse cocaine. The role of drug rehabilitation cannot be emphasized enough to prevent disease progression due to recidivism.

From the Department of General Surgery, Rush University Medical Center, Chicago, IL; and Department of Trauma and Burn, John H. Stroger, Jr. Hospital of Cook County, Chicago, IL

Address correspondence to:
James R. Yon, MD
John H. Stroger, Jr. Hospital of Cook County
1900 W. Polk Street, Suite 1300
Chicago, IL 60612
jyon@cookcountyhhs.org

Disclosure: The authors disclose no financial or other conflicts of interest.