Cocaine is used by approximately 1.5 million Americans each month and up to 69% of the cocaine seized contains levamisole. The real incidence of cocaine-levamisole induced neutropenia is unclear but probably underestimated. Associated complications include fever, thrombocytopenia, skin-vasculitis disorders, and rarely kidney injury. We present a young male, with chronic active cocaine use presenting with recurrent episodes of febrile neutropenia and thrombocytopenia. He underwent extensive work-up and was treated with many antibiotics and we suspect that his neutropenia and thrombocytopenia were caused by recurrent cocaine-levamisole use.
The etiology for neutropenia is extensive and includes medications, sepsis, and hematological or oncological conditions. Neutropenia has been well described as one of the common side effects of levamisole, an imidazothiazole previously used as an anthelminthic and adjuvant to 5-fluorouracil (5-FU) in the treatment of colon cancer [
This is relevant to physicians in New York where in 2011, in a yearly survey distributed by the Substance Abuse and Mental Health Services Administration, 2.24% of persons aged 18 years or older stated that they had used cocaine within the past year (3rd behind Rhode Island and Colorado) [
Cocaine-levamisole associated neutropenia is frequently self-limited and usually resolves after withdrawing the use of the contaminated cocaine but tends to recur with reexposure [
We present a patient with recurrent episodes of febrile neutropenia and thrombocytopenia which improved after discontinuing the use of cocaine.
A 36-year-old man was admitted to the intensive care unit with fever and right gluteal pain and swelling of three-day duration. He denied trauma, rash, flu-like symptoms, or sick contacts. Medical history included continuous cocaine abuse (sniffing), paroxysmal atrial fibrillation, and two episodes of febrile neutropenia in the past.
On examination, the patient was awake, alert, comfortable, febrile 103.1 F, and tachycardic (120 bpm) nontoxic looking. An abscess was found on the gluteal area. The rest of the skin was intact and the rest of the exam was unremarkable. Laboratory findings showed severe leucopenia with neutropenia and thrombocytopenia. Urine toxicology by immunoassay was reported to be positive for cocaine and cannabinoids.
He was managed for severe sepsis and febrile neutropenia with drainage of his gluteal abscess, fluids, broad spectrum antibiotics, including caspofungin, and granulocyte colony-stimulating factor (G-CSF). Serum and urine levamisole levels performed by high performance liquid chromatography/tandem mass spectrometry (LC-MS/MS) five days after admission were negative. Flow cytometry, cultures, serology, HIV, and vasculitis work-up were done and ruled out other common causes of neutropenia and thrombocytopenia (Table
Comparison of characteristics during the three admissions.
Admission number 1 | Admission number 2 | Current admission | |
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Presentation | Fever and sore throat | Fever, neck stiffness, cough, macular rash with whitish central papules on chest and extremities | Fever, gluteal abscess |
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WBC (ANC) | 2.8 k/uL (600 cells/uL) | 1.9 k/uL (100 cells/uL) | 1.3 k/uL (100 cells/uL) |
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Platelets lowest | 176 k/uL | 53 k/uL | 33 k/uL |
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Urine toxicology | Cocaine and cannabinoids | Cocaine | Cocaine and cannabinoids |
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Imaging | Chest X-ray-negative | Chest X-ray-negative | Chest X-ray-negative |
Chest CT negative | CT head-negative | ||
Abdomen/pelvis CT-possible colitis | CT facial bones negative | Abdomen/pelvis CT-perianal abscess | |
Echocardiogram-normal | Echocardiogram-normal | ||
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Serology-negative | HIV-negative |
HIV, HTLV, BCR-abl, malaria smear, dengue titer, hepatitis panel serum cryptococcal antigen, collagen vascular disease work-up negative, RPR | ANCA, ANA, MPO, antiphospholipid antibodies, anti-cardiolipin, complement, HLA B27, malaria, hepatitis, HIV, HTLV-all negative |
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Other tests | Flow cytometry neg. | Flow cytometry neg. | |
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Urine and serum for levamisole | Not done | Not done | Sent at day 5 of admission-negative |
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Cultures-blood, urine, stools | Negative | Negative | Negative |
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Procedures | None | Spinal tap normal | Perianal abscess drainage at the bed side |
Bone marrow biopsy ×2 | |||
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Antibiotics | Ciprofloxacin |
Vancomycin, meropenem, acyclovir, fluconazole, doxycycline, daptomycin, metronidazole, cefepime, clindamycin | Vancomycin, cefepime, |
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G-CSF (duration-days) | Not given | 5 days of administration | 8 days of administration |
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Others | Platelets transfusion | ||
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Hospital complications | None | None | Acute renal failure. Serum Creatinine |
Gastrointestinal bleeding | |||
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Fever resolution-time days | 2 days | 8 days | 7 days |
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Outcome | Discharged after 4 days-symptoms improved | Discharged after 23 days-symptoms improved | Discharged after 16 days-symptoms improved, abscess healing |
ANA = antinuclear antibodies; ANCA = antineutrophil cytoplasmic antibodies; HIV = human immunodeficiency virus; HTLV = human T-lymphotropic virus; MPO = anti-myeloperoxidase; human leukocyte antigen B27.
On review of medical records, the patient had been admitted to our institution twice during the last 12 months for febrile neutropenia. Table
Patient became afebrile on day 7 of admission with resolution of thrombocytopenia and some improvement of WBC. He was discharged home in stable condition and he was lost to follow-up.
Approximately 1.5 million Americans use cocaine each month and, according to a report from the Drug Enforcement Administration (DEA) in July 2009, 69% of the cocaine seized coming into the United States contained levamisole [
The pathophysiology of this syndrome is not completely understood, but drugs with reactive thiol groups, such as levamisole, behave as haptens and trigger immune or cytotoxic response, causing opsonization and destruction of white blood cells leading to agranulocytosis [
The most common reported complications are skin involvement with a retiform purpura with or without bullae on the helix of the ears or extremities and a self-limited neutropenia. These can occur as isolated manifestations or simultaneously. Although thrombocytopenia has been reported as an adverse effect of levamisole when used for medical purposes, a literature review of 203 cases by Larocque et al. revealed only 4 (2%) cases with thrombocytopenia. Other less common complications are fever, arthralgias, hyponatremia, and kidney injury. Although recurrence is seen with reexposure to the contaminated cocaine, it is not commonly reported [
On review of all the admissions for our patient, it is interesting to note that the nadir for the thrombocitopenia occured between day 5 and 8 and, similarly, the fever curve improved between days 5 and 8 of presentation with marginal improvement in WBC count (Figure
Graph of trend for platelets, temperature, and WBC and ANC count.
The diagnosis of cocaine-levamisole complications is a diagnosis of exclusion. It is difficult to distinguish this condition from other forms of vasculitis. A high-titer c-ANCA, p-ANCA, human neutrophil elastase ANCA (HNE-ANCA), with concomitant antinuclear, anti-phospholipid antibodies and 11 isolated skin vasculitis suggests of cocaine-levamisole as etiological agent [
Management of the condition is conservative with discontinuation of the levamisole contaminated cocaine and treatment of complications. This usually leads to a rapid clinical improvement in 2-3 weeks. Other modalities such as systemic steroids and G-CSF are also recommended without consensus about their benefits [
Cocaine-levamisole induced febrile neutropenia should be highly suspected in patients presenting with a positive cocaine test and neutropenia, vasculitis, thrombocytopenia, and positive ANCA. A careful review of prior admissions is warranted and we speculate that there is a relationship between improvement in platelets count and fever resolution in those patients.
Awareness of this entity will allow clinicians to early identify serum and urine levamisole levels and, if no readily identifiable source of fever, take these into consideration to avoid extensive and potentially costly and dangerous procedures and medications.
Patients should be advised of possible recurrence as long as they continue using these substances.
None of the authors has a financial relationship with any commercial entity that has interest in the subject of the paper.
The authors declare that there is no conflict of interests regarding the publication of this paper.