A Self Destructing Reaction to a Self Destructive Habit Levamisole tainted cocaine causing autoimmune vasculitis

Abstract

Levamisole is currently used in United States only in veterinary medicine for its antielmintic (anti-helminthic) properties. It was used in the therapy of immunitary (immunological) disorders and some type of cancers before being withdrawn from the US market in the year 2000. However, it still causes clinically significant manifestations in individuals who use cocaine preparations, which are increasingly found to be adulterated with this agent. Multiple cases of levamisole – induced vasculitis were reported in literature, but the syndrome may be much more common and underdiagnosed because of the lack of wide clinical awareness and the sometimes challenging recognition of the cocaine use in particular groups of patients. We report a case of levamisole – induced cutaneous manifestations associated with a new onset pleural effusion in a cocaine abuser, both of which subsided with abstinence from cocaine and steroid therapy. There are no similar cases of a symptomatic new onset pleural effusion present along with the classical skin manifestations.

Introduction

Levamisole is an agent previously used in humans for its immunomodulant effects in the treatment of autoimmune syndromes and later as an adjuvant in cancer therapy. However, when more efficient and less toxic drugs for the treatment of these diseases were discovered, its use was progressively reduced and the drug was eventually withdrawn from the United States market in the year 2000. Nowadays it is increasingly found in cocaine preparations, and as per recent data, it was estimated that 69% of seized cocaine in US contained levamisole. ¹

So, how could such a high prevalence in cocaine preparations be explained?

The answer is that, technically, Levamisole is not simply a tainting agent. Illicit drugs often contain unexpected substances which may be intentionally or unintentionally mixed with the drug itself, and the Levamisole may be used as an adulterant (placed intentionally in the preparation) more than a contaminant (unintentionally present) or a “cutting agent”: an agent which just expands the volume of the preparation). Some of the pharmacologic properties which have been postulated for this agent may be found to be desirable by the people implied in this market explaining the possible role as an adulterant. Levamisole is in fact an imidazothiazole which may carry nicotinic agonist properties, and this may enhance the sympathetic activity that cocaine stimulates in a synergic effect. Nicotinic receptors may also modulate the release of dopamine in the meso-limbic system through an increase of glutamatercic activity. This may translate into a stronger stimulant effect from such preparations, that along with an appearance that is similar to cocaine and an ability to bulk up crack makes this substance very convenient to add to them. ²

Levamisole – induced vasculitis can cause a painful purpuric skin rash which usually has a predilection for the ear lobes, cheeks, and extremities and is often accompanied by systemic manifestations and laboratory abnormalities such as leukopenia or neutropenia. Agranulocytosis was also reported in some cases. ^{3 4 5}

We report a case of levamisole – induced vasculitis in a cocaine abuser who presented to the hospital with skin lesions associated with a loculated pleural effusion which did not have any other plausible etiology and subsided with abstinence from cocaine and steroid therapy.

Upon reviewing the literature, pulmonary involvement such as desquamative interstitial pneumonia, hypersensitivity pneumonitis, pulmonary nodules and pulmonary hemorrhage was reported in few cases ^{6 7} but there are no cases in which the cutaneous manifestations were associated with a new-onset pleural effusion.

Case Report

A 53 years old Hispanic female presented to emergency department complaining of a rash on both arms for four days duration. The rash started in the left ear and arm followed by right arm and was associated with pain and severe pruritus.

She denied fever, chills, cough, epistaxis, hemoptysis, arthralgia, and any recent change of medications. However she admitted having a right lower subcostal pain which worsened with deep inspiration and shortness of breath.

The past medical history was significant for hypertension, diabetes, depression and similar intermittent rash for the past 7 months and a biopsy done 6 months prior to the admission showed “leukocytoclastic vasculitis”. No intervention was done at that time. There were no known allergies and her usual medications were Insulin glargine, amlodipine, quetiapine, escitalopram.

On physical examination, the patient was found to have painful palpable purpuric non well-defined plaques with surrounding erythema and bruises on lateral aspect of the proximal upper extremities, ^{[fig. 1]} which were tender to palpation. Also, morphologically similar purpuric papule were identified on superior helix of the left ear. ^{[fig. 2]} . On pulmonary exam, rales were noticed on the right base associated with pain on deep inspiration. The rest of the physical exam was unremarkable.

The laboratory tests during the hospitalization were remarkable for positive ANA (1/80), c-ANCA, CRP and an ESR of 65 mm/h. The white cell count upon admission was 4100/mcl with 74.7% Neutrophils. A test for HIV was negative, as well as multiple blood cultures.
All the other rheumatologic work up was unremarkable. ^{[fig. 3]}

Urine toxicology was positive for cocaine. The serum test for levamisole was performed on hospital day two and the result was negative. The patient initially denied any drug use, but on further interviewing during the hospital course she admitted using cocaine three days prior to admission and also reported that the last time she had similar skin lesions in the past she used cocaine prior to developing the symptoms.

An x-ray of the chest performed upon admission showed a small right side pleural effusion, which was found to be loculated on the CT chest without contrast. ^{[fig. 4]} This finding was new compared with the previous x-rays. A right upper quadrant ultrasound and an HIDA scan ruled out cholecystitis.

A thoracocentesis was done and showed results compatible with a pleural exudate but no infective agents were isolated. ^{[fig. 5]}

Punch biopsy of the skin lesion was done and showed thrombotic vasculopathy with neutrophils. ^{[fig. 7]}

The patient was started on steroids with gradual and constant clinical improvement, and dramatic amelioration of the skin lesions as well (Fig.1, Fig. 2 Right side) ^{[fig. 1] [fig. 2]} and was successfully discharged on day ten on tapering dose of steroids.

An x-ray of the chest performed eleven days after the discharge confirmed the interval resolution of the pleural effusion.

A 53 years old Hispanic female presented to emergency department complaining of a rash on both arms for four days duration. The rash started in the left ear and arm followed by right arm and was associated with pain and severe pruritus.

She denied fever, chills, cough, epistaxis, hemoptysis, arthralgia, and any recent change of medications. However she admitted having a right lower subcostal pain which worsened with deep inspiration and shortness of breath.

The past medical history was significant for hypertension, diabetes, depression and similar intermittent rash for the past 7 months and a biopsy done 6 months prior to the admission showed “leukocytoclastic vasculitis”. No intervention was done at that time. There were no known allergies and her usual medications were Insulin glargine, amlodipine, quetiapine, escitalopram.

On physical examination, the patient was found to have painful palpable purpuric non well-defined plaques with surrounding erythema and bruises on lateral aspect of the proximal upper extremities, ^{[fig. id]} which were tender to palpation. Also, morphologically similar purpuric papule were identified on superior helix of the left ear. ^{[fig. id]} . On pulmonary exam, rales were noticed on the right base associated with pain on deep inspiration. The rest of the physical exam was unremarkable.

The laboratory tests during the hospitalization were remarkable for positive ANA (1/80), c-ANCA, CRP and an ESR of 65 mm/h. The white cell count upon admission was 4100/mcl with 74.7% Neutrophils. A test for HIV was negative, as well as multiple blood cultures.
All the other rheumatologic work up was unremarkable. ^{[fig. id]}

Urine toxicology was positive for cocaine. The serum test for levamisole was performed on hospital day two and the result was negative. The patient initially denied any drug use, but on further interviewing during the hospital course she admitted using cocaine three days prior to admission and also reported that the last time she had similar skin lesions in the past she used cocaine prior to developing the symptoms.

An x-ray of the chest performed upon admission showed a small right side pleural effusion, which was found to be loculated on the CT chest without contrast. ^{[fig. id]} This finding was new compared with the previous x-rays. A right upper quadrant ultrasound and an HIDA scan ruled out cholecystitis.

A thoracocentesis was done and showed results compatible with a pleural exudate but no infective agents were isolated. ^{[fig. id]}

Punch biopsy of the skin lesion was done and showed thrombotic vasculopathy with neutrophils. ^{[fig. id]}

The patient was started on steroids with gradual and constant clinical improvement, and dramatic amelioration of the skin lesions as well (Fig.1, Fig. 2 Right side) ^{[fig. id] [fig. id]} and was successfully discharged on day ten on tapering dose of steroids.

An x-ray of the chest performed eleven days after the discharge confirmed the interval resolution of the pleural effusion.

Discussion

Cutaneous vasculitis related to the use of Levamisole adulterated cocaine preparations is a manifestation which is well known in literature and increasingly recognized by clinicians in the last years.

Interestingly, in a review of 16 similar cases there was a female predominance (81%)⁸ and this data is especially interesting if we consider that the cocaine in United States is used in in rates slightly higher for males than females⁹. The average age in the 16 previously reported cases was 43 years⁸ and here this syndrome is described in a middle aged woman as well.

In a review of the literature by Pearson et al which involved 55 cases of Levamisole –  induced vasculitis, the most common site of skin involvement was the lower extremities (46/55 patients) followed by ear involvement (40/55), which however is far more specific for this syndrome being much less frequently involved in other vascular conditions. Neutropenia was present in the 60% of the cases¹⁰. Neither neutropenia nor lower extremities involvement were present in our case, in which however several of the other typical and most frequent findings found in this syndrome were shown (skin lesions which show typical macroscopic features involving ears and upper extremities, positivity of ANA and c-ANCA, findings of thrombotic vasculitis on the skin biopsy).

This clinical syndrome remains mostly a diagnosis of exclusion, and the clinicians should be thoroughly informed about this manifestation associated with use of adulterated cocaine for a prompt recognition.

The absence of Levamisole in the serum (test performed on hospital day two) cannot rule out the Levamisole contamination since in a recent study its half life was approximately 5.6 hours¹¹. Given these limitations, recent studies show the detection of Levamisole in hair samples suggesting a possible use of this test in suspicious cases¹². Anyhow, detection of Levamisole should not be considered essential for the diagnosis in patients who recently used cocaine preparations¹³.

In this particular case, the patient also had pleuritic symptoms associated with a pleural effusion which on the analysis revealed to be an exudate, and no infection source was identified so a reactive etiology was strongly suspected. The interval resolution of the effusion eleven days after the discharge adds further evidence to this hypothesis.

There are cases of systemic vasculitis related to levamisole on literature. In one case a child who was treated with Levamisole for nephritic syndrome in 1998 developed hepatosplenomegaly and hemolytic anemia which both resolved upon the discontinuation of the agent¹⁴, A case of acute renal injury presumably related to Levamisole was reported as well¹⁵, along with cases of pulmonary involvement^{6, 7} but pleural effusions were never documented, making this the first case of Levamisole – induced vasculitis manifesting with pleuritic symptoms related to a pleural effusion along with the classical cutaneous manifestations.

The pathogenesis of this syndrome remains unclear. Levamisole has well known immunomodulating properties such as stimulating the chemotaxis of neutrophils⁶ and is possible that in predisposed individuals it may trigger an autoimmune mediated tissue damage, with the possible contribution of the vasospasm induced by the cocaine.

The best treatment strategy is unclear as well. Discontinuation of cocaine preparations use is usually followed by improvement. Steroids are commonly used to hasten recovery, but there is no consensus about their benefits in such clinical setting. The clinicians should therefore weigh the possible benefits with the risks that might be related to their administration, especially in patients at high risk for steroid-induced side effects and especially considering that there are evidences suggesting that the natural course of this disease may be self limited⁸. Steroids may be however helpful especially if signs of intense inflammation are present, even if there is no definitive data available.

The only abstinence from cocaine along with a proper counseling may prevent similar future episodes, along with preventing the more well known toxic effects of this drug.

Summary

A lack of wide clinical awareness that Levamisole is a common adulterant of cocaine preparations, along with the unwillingness of some groups of patients to admit the cocaine use and the challenging recognition of the classic features of this syndrome, can explain how Levamisole – induced vasculitis may currently be an underdiagnosed disease.
This case points the attentions the importance of a thorough history which includes possible illicit drug use that may be causing an otherwise unexplained autoimmune vasculitis.
It may also assist clinicians ameliorating the counseling skills in patients with suspected illicit drug use. The patient should be warned of the presence of possible toxic contaminants of unpredictable nature and concentration which may cause clinically relevant side effects and add further toxicity to the already potentially harmful cocaine use.