Case Presentation by Dr. Kristi Maso
A 54-year-old woman brought in by EMS presents to the ED with a 2-day history of a painful, enlarging rash over her face, ears, and extremities (rash shown below). She states the rash started on her left ear and has been spreading to her face and patches of skin on both arms. She denies any upper respiratory symptoms, shortness of breath, chest pain, abd. pain, nausea, vomiting, diarrhea, or constipation. Per EMS, who got a minimal history from the patient’s sister, the patient recently moved to Detroit 3 weeks ago to be near family. She is a known drug user (although her sister doesn’t know of what). She has a history of a heart attack 5 years ago and at that time “got some stents put in.”
ROS: negative except for current rash and “my heart races sometimes”
PMH: CAD, MI
PSH: s/p stent 5 years ago (unknown how many or what types)
Sexual history : unable to obtain, pt uncooperative
Social history: unable to obtain, pt uncooperative
Family history: unable to obtain, pt uncooperative
Physical Exam with pertinent positives:
Vitals: BP 168/105, HR 116, RR 20, T 38.1, Sp02 99% on room air, Ht 5’6, Wt 120 lbs
GEN: Thin, appears malnourished. Agitated and uncooperative, demanding pain medication
HEENT: Pupils dilated bilaterally approx. 6 mm, but are equal, round and reactive to light. EOMI. TM intact.
CVS: Tachycardic, S1, S2 with regular rhythm, no murmurs, rubs, gallops. 2+ pulses in all 4 extremities.
SKIN: Well demarcated purpuric area with an erythematous border over the left exterior ear (helix and tragus) and bilateral cheeks, crossing over the nasal bridge. + Areas of crusted, black plaques, suggesting areas of necrosis. + Tenderness to palpation over the lesions. No discharge or draining.
The remainder of the physical exam was unremarkable
12 lead EKG shows sinus tachycardia. There are Q waves in leads V4-V6. There are no ST changes or T-wave inversions. PR interval and QT interval are within normal limits.
WBC 4.1, Hgb 10.6, Hct 32.1, Plt 118 ANC .075, MCV 87.8
Na 142, K 4.3, Cl 103, HC03 22, BUN 6, Cr 1.3, Gluc. 88
PT, INR, AST, ALT, ALP – normal.
Drug screen and ETOH – pending
Muirhead TT, Eid MJ. N Engl J Med 2011; 364:e52
1) Based on the patient’s physical exam and current lab findings, which of the following would be most helpful in determining the likely etiology of the above skin lesion?
a) Order protein C & S levels
b) Follow up the urine drug screen
c) Get a sed rate and CRP
d) Order a UA
e) Repeat coags in 1 hour
2) The patient admits to using cocaine and states she recently moved to Detroit. She has been buying drugs from wherever she can. She does not have a “regular” dealer…yet. You suspect this patient has been exposed to some “bad cocaine” and that her above symptoms are likely due to her exposure to a cutting agent called levamisole. Which of the following laboratory abnormalities is often associated with this agent?
b) Elevated creatinine
3) What is the treatment for the skin lesions above?
b) Hyperbaric chamber treatment
c) Skin phototherapy
d) Cessation of drug use
e) Skin grafting
The woman above presents with signs and symptoms suggestive of Cocaine Levamisole Toxicity. Levamisole is a broad spectrum antihelmintic used in the de-worming of primarily sheep and cattle. It has been used in increasing frequency over the last decade as an adulterant or “cutting” agent in cocaine to increase profits. “Cutting” agents refer to the mixing or diluting of the illicit drug with another substance. Common agents used in the past have been rather benign in their side effects when compared to levamisole. Some of those agents include:
- Procaine, benzocaine, novacaine
- Lactose or Dextrose
- Baking soda, powdered milk, starch
Levamisole adds bulk and weight to powdered cocaine and also makes the drug appear more pure, making it an appealing adulterant for drug manufacturers trying to sell their product for the highest price. However, unlike other diluents, levamisole has some very toxic effects.
Toxic effects of levamisole
Levamisole works as a cholinergic agonist. It can cause nausea, diarrhea, dizziness, dermatitis, taste perversion, fatigue, vomiting, and arthralgias. However its major toxicity results in profound immune suppression (mechanism unknown). Severe neutropenia, defined as an absolute neutrophil count (ANC) <500, and agranulocytosis are serious side effects of patients exposed to cocaine diluted with levamisole. Agranulocytosis refers to a virtual absence of neutrophils where the ANC is lower than 100/μL (.100). An ANC less than 100 makes patients extremely vulnerable to chronic bacterial infections. Patients can present with high fever, chills, swollen glands, painful sores, and wounds that don’t heal.
The dermatitis associated with levamisole has been described as a “dead, dark, skin.” Very early, the purpura may be preceded by erythematous macules. The lesion is a vasculitis-like rash, well demarcated purpuric area with an erythematous border. There are areas of crusted, black plaques, suggesting areas of necrosis primarily over the ear(s), nose, and cheeks, but can be found on any part of the body. In dark-skinned individuals, the rash may present with deep red to brown or purple lesions. Purpura is difficult to detect in extremely dark skin people.
“Will I ever even see levamisole toxicity?”
The use of levamisole as a cutting agent in cocaine has been around in the United States since 2003 and has steadily gained popularity in the cocaine-making industry. In 2005 levamisole was found in less than two percent of all seized cocaine in the US. However, in 2009, it was found in 73.2 percent of all seized cocaine in the US. As levamisole becomes more popular, emergency departments will see larger number of patients presenting with these sometimes dangerous signs and symptoms.
Cocaine Levamisole Toxicity is a diagnosis of exclusion. And while most of the differential diagnoses are not ones that will be ruled out in the emergency department, we can make an effort to rule out some of the more severe differentials simply by obtaining a good history, paying attention to vital signs that may suggest an infectious process, and review lab studies (especially coagulation studies). Some differentials include:
- Cryoglobulinemia – check for serum IgM and IgG cryoglobulins, HCV infection.
- 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.
- 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.
Things to avoid
Patients with suspected levamisole toxicity with associated neutropenia (ANC <500) should be advised to avoid contact with people who may have colds, the flu or other contagious illness. They should not receive live vaccines or be in contact with people who have recently been vaccinated with a live vaccine.
In addition they should be cautioned to avoid the use alcohol as it may cause flushing, nausea, vomiting, headache, and facial swelling.
The only “treatment” of the dermatitis associated with levamisole toxicity is cessation of the drug. No medications (including steroids) have been associated with any improvement in skin lesions. In severe cases significant scars have remained even after cessation of drug and skin grafting has been suggested, but for cosmetic reasons only.
The blood plasma half life of levamisole is less than 6 hours but the resulting immune suppression may last up to several weeks after the patient’s last use of cocaine. This makes it difficult to diagnose levamisole toxicity as the cause of a patient’s immune suppression. However, a history of cocaine use or a positive urine drug screen for cocaine in a patient with immune suppression, and a necrotic-looking dermatitis should trigger the consideration of levamisole toxicity and a consult to toxicology. Patients should receive supportive care and proper analgesia in the ED, and if febrile, should be treated with prophylactic broad spectrum antibiotics (vancomycin and cefepime) and kept isolated as any immunosuppressed patient with febrile neutropenia would be.
- A history of cocaine use, or a positive cocaine drug screen, in combination with lab abnormalities suggestive of bone marrow suppression and a vasculitic-like rash should trigger the suspicion of Cocaine Levamisole Toxicity.
- If levamisole toxicity is suspected based on skin lesions and history of drug use, a CBC with differential should be ordered to evaluate ANC and look for severe neutropenia or agranulocytosis.
- Severe neutropenic patients (ANC <500) with a fever should: 1) wear a mask, 2) be started on broad spectrum antibiotics, and 3) be kept in isolation.
- Supportive therapy and prophylactic antibiotic therapy (if indicated) are mainstays of treatment in the ED. Cessation of the drug is the only “cure.”
- Contact toxicology, as the true incidence of Cocaine Levamisole Toxicity is difficult to track and it’s important from an epidemiology standpoint to get toxicology involved.
Erowid Crew. “Cocaine Adulterated with Levamisole on the Rise: Status as of September 2009” Erowid.org. Oct 1, 2009. http://www.erowid.org/cocaine/cocaine_article2.shtml
Farnier, C. Agranulocytosis Associated with Cocaine Use. Morbidity and Mortality Weekly Report, Dec. 8, 2009. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5849a3.htm
Muirhead TT, Eide MJ. N Engl J Med 2011;364:e52
Szalavitz, M. “A Common Cut in Cocaine May Prove Deadly.” Time Magazine, Jan. 10,2010. http://www.time.com/time/health/article/0,8599,1955112,00.html