Levamisole is an antihelminthic and immunomodulator medication that was banned by the USFDA in 1998. It has been increasingly used to adulterate cocaine due to its psychotropic effects and morphological properties. Adverse reactions including cutaneous vasculitis, thrombocytopenia, and agranulocytosis have been well described. Despite systemic vasculitis in this setting, renal involvement is uncommon. We report here a case of ANCA positive systemic vasculitis with biopsy proven immune complex mediated glomerulonephritis likely secondary to levamisole/cocaine. A 40-year-old Caucasian male with no past medical history presented with 3-week history of fatigue, skin rash, joint pains, painful oral lesions, oliguria, hematuria, worsening dyspnea on exertion, and progressive lower extremity edema. He had a history of regular tobacco and cocaine use. Lab testing revealed severe anemia, marked azotemia, deranged electrolytes, and 4.7 gm proteinuria. Rheumatologic testing revealed hypocomplementemia, borderline ANA, myeloperoxidase antibody, and positive atypical p-ANCA. Infectious and other autoimmune workup was negative. Kidney biopsy was consistent with immune mediated glomerulonephritis and showed mesangial proliferation and immune complex deposition consisting of IgG, IgM, and complement. High dose corticosteroids and discontinuing cocaine use resulted in marked improvement in rash, mucocutaneous lesions, and arthritis. There was no renal recovery and he remained hemodialysis dependent.
Levamisole is an antihelminthic and immunomodulator medication previously used to treat steroid resistant nephrotic syndrome in pediatric population and also as adjuvant chemotherapy for colorectal and breast cancer [
A 40-year-old Caucasian male with no past medical history presented to the emergency room with one-week history of progressive shortness of breath on exertion. He also complained of palpitations, fatigue, and orthopnea. In addition, he complained of progressive lower extremity swelling for the last 3 weeks and multiple painful ulcerations on his tongue and in his mouth for 2 weeks. History was also notable for multiple joint pains for 6 months. He was diagnosed with Lyme’s disease and was treated with high dose doxycycline for 2 months. Two months prior to admission, he noticed diffuse nonitchy rash on his chest, back, abdomen, arms, and legs that subsequently resolved. One month prior to admission, he noticed decreased urine output and dark colored urine. There was no history of fever, chills, weight loss, night sweats, cough, chest pain, or hemoptysis. He denied having any dry eyes, oral ulcers, photosensitivity, abdominal pain, hematuria, dysuria, or neurologic symptoms.
Medications included doxycycline and ibuprofen. He had history of long standing tobacco abuse, alcohol use, and regular cocaine use. He denied having any tattoos, sick contacts, recent travel, or environmental or occupational exposure.
On examination, he was afebrile, tachycardic, tachypneic, and hypoxic on room air. The tongue had hyperkeratotic, hyperpigmented papules. There were scattered erythematous maculopapular lesions on the chest. He had bilateral lower extremity edema with skin changes suggestive of chronic venous stasis and prominent symmetric synovitis of metacarpophalangeal and wrist joints. Chest auscultation revealed diffuse rales bilaterally. Cardiovascular, abdominal, and neurologic examinations were unremarkable.
Lab results are shown in Table
Lab results.
Variable | Result on admission (reference range) | Result at discharge (reference range) |
---|---|---|
White cell count | 12.7 (3.5–10.1) | 5.7 (3.5–10.1) |
Neutrophils % | 10.8 (1.6–7.2) | 4.6 (1.6–7.2) |
Lymphocytes % | 1.4 (1.1–4.0) | 0.8 (1.1–4.0) |
Eosinophils % | 0.1 (0.0–0.4) | 0.0 (0.0–0.4) |
Basophils % | 0.1 (0.0–0.1) | 0.0 (0.0–0.1) |
Monocytes % | 0.3 (0.0–0.9) | 0.3 (0.0–0.9) |
Hemoglobin, g/dL | 6.1 (13.5–17.0) | 9.4 (13.5–17.0) |
Platelet count | 334 (150–400) | 267 (150–400) |
Sodium mmol/L | 120 (135–145) | 138 (135–145) |
Potassium mmol/L | 6.9 (3.5–5.2) | 4.6 (3.5–5.2) |
Chloride mmol/L | 87 (95–107) | 100 (95–107) |
Carbon dioxide mmol/L | 10 (21–31) | 24 (21–31) |
Blood urea nitrogen mg/dL | 195 (8–22) | 67 (8–22) |
Creatinine mg/dL | 20.83 (0.60–1.40) |
6.77 (0.60–1.40) |
Calcium mg/dL | 5.6 (8.5–10.5) | 8.6 (8.5–10.5) |
Phosphorus mg/dL | 20.2 (2.3–4.3) | 5.8 (2.3–4.3) |
Aspartate aminotransferase, U/L | 721 (10–37) | 39 (10–37) |
Alanine aminotransferase, U/L | 252 (9–47) | 62 (9–47) |
Alkaline phosphatase, U/L | 146 (30–110) | 113 (30–110) |
Total bilirubin, mg/dL | 0.8 (0.3–1.2) | 0.3 (0.3–1.2) |
Albumin, g/dL | 2.9 (3.5–5.1) | 3.4 (3.5–5.1) |
Protein, g/dL | 5.3 (6.4–8.6) | 5.3 (6.4–8.6) |
International normalized ratio | 1.7 | 1.1 |
Partial thromboplastin time, sec | 44.1 (25.0–32.0) | 28.8 (25.0–32.0) |
Urine protein/creatinine ratio | 4.7 (0.0–0.2) | |
Urinalysis | 3+ protein, 2+ blood, 10–20 RBC, and Hyaline and RBC cast | |
ESR, mm/hr | 61 (0–20) | |
CRP mg/dL | 7.4 (0.0–1.0) | |
Complement C3, mg/dL | 42 (70–176) | |
Complement C4, mg/dL | 7.7 (12.1–42.9) | |
Anti-nuclear antibodies, IU/mL | <1 : 160 (<1 : 160) | Negative (<1 : 160) |
Anti-double-stranded DNA, IU/mL | 6.6 (0.0–29.9) | |
Anti-neutrophil cytoplasmic antibody | 1 : 640 p-ANCA (<1 : 20) | |
Anti-SSA, U | 0.9 (<20) | |
Myeloperoxidase antibody, U | 2.8 (<0.4) | |
Proteinase-3 auto antibody, U | 0.4 (<0.4) | |
Cryoglobulin screen | Negative | |
Lupus anticoagulant | Negative | |
Serum and protein electrophoresis | Negative for monoclonal antibodies | |
Tuberculin skin test | Negative | |
HIV-1 and HIV-2 antibodies | Negative | |
Acute hepatitis panel | Negative for hepatitis B and hepatitis C | |
Rapid plasma reagin | Negative | |
Histoplasma urine antigen | Negative | |
Blood and urine cultures | Negative |
Kidney biopsy showed diffuse tubulointerstitial fibrosis with the majority of glomeruli globally sclerosed. Few intact glomeruli showed mesangial proliferation and immune complex deposition consisting of IgG, IgM, and complement in mesangial and endocapillary distribution. It was consistent with immune mediated glomerulonephritis (Figure
(a) Masson trichrome stain (100x) revealed severe interstitial fibrosis, thickened arterioles, and mild proliferation of glomeruli. (b) PAS stain (600x) showed mild mesangial proliferation and segmental sclerosis. No extra capillary crescent or necrosis was identified. Six of 10 glomeruli were globally sclerosed. (c) IF showed 2-3+ IgG and C3 deposit mainly in mesangium and also along the capillary loops. (d) Electron microscopy showed intramembranous and subepithelial electron dense deposits with occasional subendothelial and mesangial deposits. There were segmental foot process effacement and focal mesangial interposition.
Given the clinical, laboratory, and pathologic findings, we concluded that the ANCA associated systemic vasculitis and immune complex mediated glomerulonephritis were secondary to levamisole/cocaine use.
He required mechanical ventilation for acute hypoxic and hypercarbic respiratory failure. He was placed on continuous renal replacement therapy for severe azotemia with multiple electrolyte abnormalities including hyperkalemia. He was started on high dose steroids with marked improvement in his rash, mucocutaneous lesions, and arthritis. There was no renal recovery and he remained hemodialysis dependent. He was discharged on prednisone 40 mg daily, slowly tapered, and stopped after 3 months with resolution of arthritis and skin rash. Repeat rheumatologic workup was negative for ANCA after 3 months of steroid therapy and cocaine abstinence. He is currently undergoing intermittent hemodialysis and is awaiting renal transplant.
Levamisole contamination of cocaine has become a widespread health problem. In 2009, nearly two-thirds of cocaine samples seized by the DEA in the US [
Earliest cases of levamisole induced necrotizing cutaneous vasculitis were reported in 1970s by Scheinberg et al. and Macfarlane and Bacon [
Cocaine itself has been associated with ANCA positive cutaneous vasculitis but systemic organs are rarely affected [
First description of levamisole induced nephropathy was as early as in 1978 when Hansen et al. described a case of rheumatoid arthritis treated with levamisole developing a pruritic rash, leukopenia, thrombocytopenia, and proteinuria [
Renal involvement is relatively uncommon with ANCA positive vasculitis caused by levamisole/cocaine. To the best of our knowledge, this may be the second reported case with biopsy proven immune complex mediated glomerulonephritis. Rheumatologic workup in our patient was positive for atypical p-ANCA, myeloperoxidase antibody, and hypocomplementemia. In the presence of adequate exposure, these abnormalities are now increasingly recognized as very specific for levamisole-adulterated cocaine exposure [
This case illustrates the growing issue of cocaine abuse and levamisole contamination. Levamisole induced vasculitis is a diagnosis of exclusion but should be considered in cocaine users presenting with vasculitis, arthralgia, leukopenia, and positive ANCA titers after excluding infections and other idiopathic vasculitides. Timely recognition of this clinical entity is important to avoid misdiagnosis and unnecessary prolonged treatment with harmful cytotoxic agents as discontinuation of cocaine use could result in resolution of symptoms.
Antinuclear antibody
Perinuclear anti-neutrophilic cytoplasmic antibody
US Food and Drug Administration
Erythrocyte sedimentation rate
C-reactive protein
B-natriuretic peptide
Parathyroid hormone
Anti-myeloperoxidase antibody.
All the authors have no conflict of interests and nothing to disclose.
All authors have contributed to this paper and reviewed, and approved the current form of the paper to be submitted.