Levamisole-induced vasculitis is a characteristic cutaneous vasculitis syndrome associated with the use of levamisole-adulterated cocaine. Patients will typically present with a painful, purpuric rash in a retiform or stellate pattern with or without central necrosis involving the extremities, trunk, nasal tip, digits, cheeks, and/or ears. A history of cocaine abuse can be elicited. Histologic features include microvascular thrombi and/or leukocytoclastic vasculitis involving small vessels of the superficial and deep dermis. Epidermal involvement is variably seen. Laboratory findings include leukopenia, neutropenia (including agranulocytosis), elevated erythrocyte sedimentation rate, normal coagulation studies, and positive autoantibodies including perinuclear and cytoplasmic antineutrophil cytoplasmic antibodies, antinuclear antibody, and lupus anticoagulant. Differential diagnosis includes other microscopic vasculitides, and clinical and laboratory correlation with histologic findings is essential. Lesions typically resolve with the cessation of cocaine use. Because of the treatment implications and rising incidence of this entity, rapid and accurate diagnosis is essential.

Levamisole is a veterinary antihelminthic drug that, in the past, was a US Food and Drug Administration–approved drug in humans used to treat various cancers and rheumatoid arthritis because of its immunomodulating effects.1,2  The Food and Drug Administration banned the use of levamisole in the United States in 2000 because of adverse side effects including agranulocytosis and vasculitis.3,4  However, reports began surfacing around late 2009 and early 2010 about a characteristic cutaneous vasculitis found in cocaine users associated with neutropenia and positive antineutrophil cytoplasmic antibodies (ANCAs).510  Soon after, researchers isolated levamisole using urine toxicology and gas chromatography–mass spectrometry studies in patients with suspected levamisole-induced vasculitis, confirming prior suspicions that it was in fact the etiologic agent.11,12  Approximately 70% of the cocaine in the United States contains levamisole, which is used to add volume and weight to the drug and possibly to potentiate the psychotropic effects of cocaine.3,13,14  Levamisole has been detected in cocaine since 2003, and detection has only increased in recent years.14,15  Levamisole-induced vasculitis was originally described in 1978 in a patient being treated for rheumatoid arthritis and has been described in children receiving treatment for nephrotic syndrome.2,4  However, because levamisole is no longer in clinical use, the reported cases today are exclusively from users of levamisole-adulterated cocaine. Because of the unique clinical picture and treatment implications, pathologists should be aware of this diagnostic entity.

CLINICAL FEATURES

Levamisole-induced vasculitis has predilection for women (male to female ratio, 1:3) with mean age of presentation of 44 years.12  Patients typically present with a tender, purpuric rash in a retiform or stellate pattern with or without central necrosis involving the extremities, trunk, nasal tip, digits, cheeks, and/or ears (Figure 1).7,16  Bulla formation is not uncommon and, with subsequent skin sloughing, bacterial superinfection can increase morbidity.12  Lesions of the ear and digits have been reported to self-amputate.12  In addition to the cutaneous manifestations, laboratory findings include leukopenia, neutropenia (including agranulocytosis), elevated erythrocyte sedimentation rate, normal coagulation studies, and positive autoantibodies including perinuclear and cytoplasmic ANCAs (p- and c-ANCAs), antinuclear antibody, and lupus anticoagulant.7,11,17 

Figure 1. 

Retiform and stellate purpura with and without central necrosis is typically seen grossly.

Figure 1. 

Retiform and stellate purpura with and without central necrosis is typically seen grossly.

PATHOLOGIC FEATURES

The two classic pathologic findings include (1) leukocytoclastic vasculitis of small vessels consisting of fibrinoid necrosis of the vessel wall, extravasated erythrocytes, karyorrhectic debris, and angiocentric inflammation and (2) multiple fibrin thrombi within small vessels in the superficial and deep dermis (Figures 2 through 5). Classically, both of these histologic findings are present; however, it is not uncommon to have only one or the other present. The presence of microvascular fibrin thrombi appears to be the most consistent histologic feature.7,12  Some authors have purported that the presence of both microvascular fibrin thrombi and leukocytoclastic vasculitis may be relatively specific for levamisole-induced vasculitis.11  Fibrin thrombi may show a spectrum of early fibrinous plugs to well-organized fibrous thrombi, reflecting the repeated insults from chronic levamisole-adulterated cocaine use.11  The epidermis may or may not show changes depending on the location of the biopsy. Epidermal changes, if present, include suprabasilar bulla formation, full-thickness epidermal necrosis, and ulceration.6,11,16,18  Some authors have described extensive interstitial and perivascular neovascularization; however, this finding is rarely seen.18  Bone marrow biopsies for patients with the additional clinical finding of agranulocytosis show myeloid hypoplasia, mild megakaryocyte hyperplasia, and increased bone marrow plasma cells with circulating plasmacytoid lymphocytes in the peripheral blood, all of which can be helpful in distinguishing cocaine-related versus non–cocaine-related causes of agranulocytosis.17,19 

Figure 2. 

Punch biopsy shows an unremarkable epidermis overlying superficial and deep dermal perivascular inflammation (hematoxylin-eosin, original magnification ×20).

Figure 3. There are numerous fibrin thrombi present within superficial dermal vessels (arrows) with associated leukocytoclastic vasculitis with extravasated erythrocytes, perivascular neutrophils, and nuclear “dust.” The epidermis is intact (hematoxylin-eosin, original magnification ×100).

Figure 4. Multiple fibrin thrombi are present within the deeper dermal vessels. Areas of fibrinoid necrosis of the vessel wall are seen (arrow) with an associated brisk, perivascular mixed inflammatory infiltrate (hematoxylin-eosin, original magnification ×200).

Figure 5. Intense perivascular mixed inflammation consisting of macrophages and neutrophils with associated mural thrombin deposition and an organizing thrombus (hematoxylin-eosin, original magnification ×400).

Figure 2. 

Punch biopsy shows an unremarkable epidermis overlying superficial and deep dermal perivascular inflammation (hematoxylin-eosin, original magnification ×20).

Figure 3. There are numerous fibrin thrombi present within superficial dermal vessels (arrows) with associated leukocytoclastic vasculitis with extravasated erythrocytes, perivascular neutrophils, and nuclear “dust.” The epidermis is intact (hematoxylin-eosin, original magnification ×100).

Figure 4. Multiple fibrin thrombi are present within the deeper dermal vessels. Areas of fibrinoid necrosis of the vessel wall are seen (arrow) with an associated brisk, perivascular mixed inflammatory infiltrate (hematoxylin-eosin, original magnification ×200).

Figure 5. Intense perivascular mixed inflammation consisting of macrophages and neutrophils with associated mural thrombin deposition and an organizing thrombus (hematoxylin-eosin, original magnification ×400).

The exact pathogenesis of levamisole-induced vasculitis is currently uncertain.7,12,20  An immune complex–mediated process is the favored hypothesis based on immunofluorescence studies in the skin.6,7  For the agranulocytosis, studies have suggested that levamisole may act as a hapten causing formation of antibodies to various leukocyte antigens, leading to opsonization and subsequent destruction of neutrophils, and may also account for the development of autoantibodies.19,21 

LABORATORY FINDINGS

Laboratory findings in patients with levamisole-induced vasculitis include leukopenia (leukocyte count <4000/μL), neutropenia (neutrophil count <1500/μL), agranulocytosis (neutrophil count <500/μL), elevated erythrocyte sedimentation rate, normal coagulation studies, and positive autoantibodies including p- and c-ANCAs, anti-nuclear antibody, and lupus anticoagulant. The specificity of the ANCA involved can be useful in differentiating among other vasculitides such as granulomatous polyangiitis (formerly Wegener granulomatosis), microscopic polyangiitis, and Churg-Strauss granulomatosis. By indirect immunofluorescence, two classic patterns are seen on cytospin-prepared, ethanol-fixed neutrophils.22  Anti-neutrophil cytoplasmic antibodies directed against proteinase 3 produce a cytoplasmic pattern reflected in the term c-ANCA. Anti-neutrophil cytoplasmic antibodies directed against myeloperoxidase typically produce a perinuclear pattern (p-ANCA).23  Results of indirect immunofluorescence are confirmed by the performance of antigen-specific immunoassays for proteinase 3 and myeloperoxidase ANCAs.23  The presence of c-ANCA is usually seen in granulomatous polyangiitis, and p-ANCA is usually seen in microscopic polyangiitis. However, so-called atypical ANCAs exist because of other neutrophil granule constituents (including human neutrophil elastase, azurocidin, lactoferrin, and lysozyme), which cause inconsistent fluorescence patterns.24  Elevated levels of antibodies against human neutrophil elastase have been strongly associated with cocaine-induced lesions.25  Thus, antibody specificities of ANCAs may play a discriminatory role in the diagnosis of levamisole-induced vasculitis.11,25  Lastly, the half-life of levamisole is 5.6 hours, and it can be detected by gas chromatography–mass spectrometry, although this is not necessary for diagnosis.26  Screening for cocaine use can be accomplished through a urine enzyme immunoassay, which typically detects cocaine metabolites benzoylecgonine and m-hydroxybenzoylecgonine. Confirmation of cocaine use is typically performed using a quantitative gas chromatography–mass spectrometry or quantitative liquid chromatography–tandem mass spectrometry test to quantify the cocaine metabolite benzoylecgonine in samples of urine, serum, or plasma. Testing for levamisole has been performed using mass spectrometry,13  but is not required because of the high prevalence of levamisole in cocaine and the fact that the diagnosis can be made in the context of the other clinical, pathologic, and laboratory findings.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis includes ANCA-associated vasculitides (granulomatous polyangiitis, microscopic polyangiitis, Churg-Strauss syndrome), septic vasculitis, disseminated intravascular coagulation, cryoglobulinemia, warfarin-induced skin necrosis, and heparin-induced thrombocytopenia.6,7  All of these can present clinically with palpable, retiform purpura similar to that seen in levamisole-induced vasculitis. Granulomatous polyangiitis typically shows small vessel vasculitis with poorly formed granulomatous inflammation. Microvascular fibrin thrombi can also be seen. Clinically, patients will often have lung and/or kidney involvement. Antibodies against c-ANCA with anti–proteinase 3 specificity are usually seen. Microscopic polyangiitis will show small vessel leukocytoclastic vasculitis, and patients usually have renal involvement, with p-ANCA antibodies (with antimyeloperoxidase specificity) identified. Churg-Strauss usually presents in young adults and shows a mixed inflammatory small vessel vasculitis with numerous eosinophils, neutrophils, and granulomatous inflammation. It is strongly associated with asthma and peripheral eosinophilia. It is important to recognize that there is a great deal of histologic overlap between the microscopic vasculitides and clinical correlation is essential for accurate diagnosis.

CURRENT TREATMENT AND PROGNOSIS

The ideal treatment for levamisole-induced vasculitis has not been determined; however, nearly all cases resolve upon the cessation of cocaine use.7,11,12  The role of corticosteroids is not well defined; these have not definitively been shown to improve or accelerate healing.7,11,27  Use of plasmapheresis has been investigated but only in case reports.27  Some patients develop bacterial superinfection of the lesions after rupture of bullae, leading to complications such as extensive wound infections requiring surgical debridement and subsequent skin grafting.12,27  This is further exacerbated by the fact that neutropenia and leukopenia is common in these patients, causing an induced immune-suppressed state. There are some reports of patients with such severe wounds that they necessitate amputation.9,12  Because of the strong association with neutropenia and risk of bacterial infections of wounds, it may be prudent to avoid corticosteroids because of the immunosuppressive effects and the paucity of data related to their effectiveness. This is where it is critical for pathologists to be aware of this entity so that the correct treatment regimen can be started earlier rather than later in an effort to avoid the aforementioned morbid sequelae. This is especially true considering entities in the differential diagnosis are generally treated with corticosteroids.

CONCLUSION

In summary, levamisole-induced vasculitis is a cutaneous vasculitis syndrome associated with the use of levamisole-adulterated cocaine. Patients will typically present with a painful, purpuric rash in a retiform or stellate pattern with or without central necrosis involving the extremities, trunk, nasal tip, digits, cheeks, and/or ears. A history of cocaine abuse can be elicited. Characteristic histologic features include microvascular thrombi and/or leukocytoclastic vasculitis involving small vessels of the superficial and deep dermis, with fibrin thrombi the most consistent finding. Epidermal involvement is variably seen depending on the location of the biopsy. Laboratory studies can show leukopenia, neutropenia (including agranulocytosis), elevated erythrocyte sedimentation rate, normal coagulation studies, and positive autoantibodies including p- and c-ANCA, anti-nuclear antibody, and lupus anticoagulant. The differential diagnosis encompasses other microscopic vasculitides including granulomatous polyangiitis (formerly known as Wegener granulomatosis), microscopic polyangiitis, and Churg-Strauss syndrome. Therefore, clinical and laboratory correlation with histologic findings is essential for diagnosis and treatment (Table). Resolution of symptoms is seen with the cessation of cocaine use. Because of the treatment implications and increasing incidence of this entity, rapid and accurate diagnosis is essential.

Summary of Clinical, Histologic, and Laboratory Findings Plus Treatment of Levamisole-Induced Vasculitis

Summary of Clinical, Histologic, and Laboratory Findings Plus Treatment of Levamisole-Induced Vasculitis
Summary of Clinical, Histologic, and Laboratory Findings Plus Treatment of Levamisole-Induced Vasculitis

References

1
Parkinson
DR
,
Cano
PO
,
Jerry
LM
,
et al
.
Complications of cancer immunotherapy with levamisole
.
Lancet
.
1977
;
1
(
8022
):
1129
1132
.
2
Macfarlane
DG
,
Bacon
PA.
Levamisole-induced vasculitis due to circulating immune complexes
.
Br Med J
.
1978
;
1
(
6110
):
407
408
.
3
Centers for Disease Control and Prevention (CDC)
.
Agranulocytosis associated with cocaine use—four states, March 2008–November 2009
.
MMWR Morb Mortal Wkly Rep
.
2009
;
58
(
49
):
1381
1385
.
4
Rongioletti
F
,
Ghio
L
,
Ginevri
F
,
et al
.
Purpura of the ears: a distinctive vasculopathy with circulating autoantibodies complicating long-term treatment with levamisole in children
.
Br J Dermatol
.
1999
;
140
(
5
):
948
951
.
5
Chen
SC
,
Jang
MY
,
Wang
CS
,
et al
.
Cocaine-related vasculitis causing scrotal gangrene
.
Ann Pharmacother
.
2009
;
43
(
2
):
375
378
.
6
Waller
JM
,
Feramisco
JD
,
Alberta-Wszolek
L
,
McCalmont
TH
,
Fox
LP.
Cocaine-associated retiform purpura and neutropenia: is levamisole the culprit?
J Am Acad Dermatol
.
2010
;
63
(
3
):
530
535
.
7
Chung
C
,
Tumeh
PC
,
Birnbaum
R
,
et al
.
Characteristic purpura of the ears, vasculitis, and neutropenia—a potential public health epidemic associated with levamisole-adulterated cocaine
.
J Am Acad Dermatol
.
2011
;
65
(
4
):
722
725
.
8
Farhat
EK
,
Muirhead
TT
,
Chaffins
ML
,
Douglass
MC.
Levamisole-induced cutaneous necrosis mimicking coagulopathy
.
Arch Dermatol
.
2010
;
146
(
11
):
1320
1321
.
9
Mouzakis
J
,
Somboonwit
C
,
Lakshmi
S
,
et al
.
Levamisole induced necrosis of the skin and neutropenia following intranasal cocaine use: a newly recognized syndrome
.
J Drugs Dermatol
.
2011
;
10
(
10
):
1204
1207
.
10
Ullrich
K
,
Koval
R
,
Koval
E
,
Bapoje
S
,
Hirsh
JM.
Five consecutive cases of a cutaneous vasculopathy in users of levamisole-adulterated cocaine
.
J Clin Rheumatol
.
2011
;
17
(
4
):
193
196
.
11
Walsh
NM
,
Green
PJ
,
Burlingame
RW
,
Pasternak
S
,
Hanly
JG.
Cocaine-related retiform purpura: evidence to incriminate the adulterant, levamisole
.
J Cutan Pathol
.
2010
;
37
(
12
):
1212
1219
.
12
Arora
NP
,
Jain
T
,
Bhanot
R
,
Natesan
SK.
Levamisole-induced leukocytoclastic vasculitis and neutropenia in a patient with cocaine use: an extensive case with necrosis of skin, soft tissue, and cartilage
.
Addict Sci Clin Pract
.
2012
;
7
(
1
):
19
.
13
Buchanan
JA
,
Heard
K
,
Burbach
C
,
Wilson
ML
,
Dart
R.
Prevalence of levamisole in urine toxicology screens positive for cocaine in an inner-city hospital
.
JAMA
.
2011
;
305
(
16
):
1657
1658
.
14
Chang
A
,
Osterloh
J
,
Thomas
J.
Levamisole: a dangerous new cocaine adulterant
.
Clin Pharmacol Ther
.
2010
;
88
(
3
):
408
411
.
15
Knowles
L
,
Buxton
JA
,
Skuridina
N
,
et al
.
Levamisole tainted cocaine causing severe neutropenia in Alberta and British Columbia
.
Harm Reduct J
.
2009
;
6
:
30
.
16
Bradford
M
,
Rosenberg
B
,
Moreno
J
,
Dumyati
G.
Bilateral necrosis of earlobes and cheeks: another complication of cocaine contaminated with levamisole
.
Ann Intern Med
.
2010
;
152
(
11
):
758
759
.
17
Czuchlewski
DR
,
Brackney
M
,
Ewers
C
,
et al
.
Clinicopathologic features of agranulocytosis in the setting of levamisole-tainted cocaine
.
Am J Clin Pathol
.
2010
;
133
(
3
):
466
472
.
18
Jacob
RS
,
Silva
CY
,
Powers
JG
,
et al
.
Levamisole-induced vasculopathy: a report of 2 cases and a novel histopathologic finding
.
Am J Dermatopathol
.
2012
;
34
(
2
):
208
213
.
19
Thompson
JS
,
Herbick
JM
,
Klassen
LW
,
et al
.
Studies on levamisole-induced agranulocytosis
.
Blood
.
1980
;
56
(
3
):
388
396
.
20
Magro
CM
,
Wang
X.
Cocaine-associated retiform purpura: a C5b-9-mediated microangiopathy syndrome associated with enhanced apoptosis and high levels of intercellular adhesion molecule-1 expression
.
Am J Dermatopathol
.
2013
;
35
(
7
):
722
730
.
21
Raymon
LP
,
Isenschmid
DS.
Letter to the editor: the possible role of levamisole in illicit cocaine preparations
.
J Anal Toxicol
.
2009
;
33
(
9
):
620
622
.
22
van der Woude
FJ
,
Rasmussen
N
,
Lobatto
S
,
et al
.
Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis
.
Lancet
.
1985
;
1
(
8426
):
425
429
.
23
Savige
J
,
Gillis
D
,
Benson
E
,
et al
.
International consensus statement on testing and reporting of antineutrophil cytoplasmic antibodies (ANCA)
.
Am J Clin Pathol
.
1999
;
111
(
4
):
507
513
.
24
Hoffman
GS
,
Specks
U.
Antineutrophil cytoplasmic antibodies
.
Arthritis Rheum
.
1998
;
41
(
9
):
1521
1537
.
25
Wiesner
O
,
Russell
KA
,
Lee
AS
,
et al
.
Antineutrophil cytoplasmic antibodies reacting with human neutrophil elastase as a diagnostic marker for cocaine-induced midline destructive lesions but not autoimmune vasculitis
.
Arthritis Rheum
.
2004
;
50
(
9
):
2954
2965
.
26
Zhu
NY
,
Legatt
DF
,
Turner
AR.
Agranulocytosis after consumption of cocaine adulterated with levamisole
.
Ann Intern Med
.
2009
;
150
(
4
):
287
289
.
27
Pavenski
K
,
Vandenberghe
H
,
Jakubovic
H
,
Adam
DN
,
Garvey
B
,
Streutker
CJ.
Plasmapheresis and steroid treatment of levamisole-induced vasculopathy and associated skin necrosis in crack/cocaine users
.
J Cutan Med Surg
.
2013
;
17
(
2
):
123
128
.

Author notes

The authors have no relevant financial interest in the products or companies described in this article.