Via Research Recognition Day 2024 VCOM-Carolinas

Clinical Case-Based Reports

Levamisole-Adulterated Cocaine Causing Leukocytoclastic Vasculitis and Potential Display of Anti-Tumor Effects Against Lung Tumor Cell Growth Rachel Hemsath OMS-III, Shannon Leonard OMS-III, Debra Miller-Cox MD Edward Via College of Osteopathic Medicine - Carolinas Campus, Spartanburg, SC

Abstract

Case

Discussion/Conclusions

Levamisole is a drug that originated for use in veterinary medicine as an anthelmintic medication but was also found to have benefits in treating cancers and autoimmune diseases in humans. Specifically, levamisole was used in conjunction with other chemotherapies to treat lung cancer, as it had anti-tumor effects such as reducing the number and cell cycle function of cancer cells. Although found to have therapeutic benefits, levamisole’s harmful effects of causing agranulocytosis and leukocytoclastic vasculitis (LV) is what led to it being removed from the markets in the year 2000. Since then, reports of unexplained agranulocytosis and LV were seen in cocaine users due to levamisole being used as a common cutting agent. This case focuses on a 53-year-old African American woman with a chronic history of tobacco and cocaine abuse who suffered from multiple cases of LV induced by cocaine laced with levamisole. What is unique in this case is that the patient eventually quit using cocaine but less than two years later presented with a 60-pound weight loss and large mass in the upper right lung, later confirmed to be small cell lung carcinoma. Given levamisole’s previous role in lung cancer therapy, we theorize that this patient’s chronic cocaine use, and therefore levamisole exposure, may have suppressed or slowed her tumor development. Levamisole is a drug that was approved in 1990 by the Food and Drug Administration (FDA) for its anti-cancer effects. It is an imidazothiazole derivative that was initially - developed as an anthelmintic for veterinary medicine but was later found useful in conjunction with 5-fluorouracil to target cancer in humans. Its anti-tumor effects, especially in the lungs, reduce the cell cycle function of cancer cells and was known for reducing recurrences and metastases, while increasing survival time of patients. Although it has been shown to have benefits as an antineoplastic agent and antihelminthic drug, its side effect profile has limited its widespread use in humans leading to its removal from the markets in 2000. Primarily causing agranulocytosis and LV, its toxic effects are reported to be dose dependent and more significant when chronically used rather than with short-term use as seen in Figures 1 & 2 . After being removed from the market, reports of unexplained agranulocytosis in patients were being discovered, with the commonality being that these patients were the use of cocaine laced with levamisole. Because levamisole has a similar consistency to cocaine, dealers were able to increase their profits by cutting their batches with levamisole in order to increase profits. Estimated by the Drug Enforcement Agency (DEA) in 2009, there were approximately 69% of cocaine samples tested that contained levamisole, with more recent studies determining the amount to be as high as 80%. Unfortunately, according to the DEA’s database analysis, the annual amount of levamisole only increases each year. Introduction

● Levamisole works to enhance the immune response and encourage the body to fight against cancerous cells by activating the response of macrophages and neutrophils, upregulating toll-like receptors and human leukocyte antigen (HLA)-DR molecules on cell surfaces, increasing cytokines that activate dendritic cells and inducing differentiation of T cells towards TH1, encouraging apoptosis by arresting the cell cycle in the G0/G1 phase, and enhancing TRAIL-induced DR4 independent apoptosis by inhibiting phosphorylation of cJUN. ● Levamisole had known properties of suppressing lung and colon cancers, however the side effects of agranulocytosis and LV as a result of the enhanced immune response were too severe and had unfortunate consequences, as seen in this patient. ● This case is unique in the fact that it is one of the few documented cases of LV in which a person with African American race has been reported. In the future, more research should be conducted on racial and genetic predisposition and susceptibility to vasculitides as a result of the use of levamisole. ● This case also raises the question of whether or not her chronic cocaine use, and therefore levamisole exposure, could have potentially suppressed any lung cancer cells from proliferating. Given her long smoking history, she as at increased risk of developing small cell lung carcinoma (SCLC), however it is important to emphasize that her chest imaging and scans throughout the first 6 years were negative. It was only after the cessation of cocaine adulterated with levamisole that she presented with a rapid progression of SCLC. ● Further research may be beneficial in exploring the use of levamisole to prevent and decrease lung tumor development with emphasis on ways to minimize the risk of adverse effects this drug causes. ● Disclaimer : In no way does this case encourage the use of levamisole for lung cancer or tumor suppression seeing as the FDA removed this drug to protect against the harmful side effects, which are apparent in the multiple hospitalizations and severity of illness that this patient had throughout her exposure. Our goal is to present a case of LV caused by levamisole laced in cocaine, and simply point out the observation that levamisole’s previous use for lung cancer suppression may have played a roll in this patient’s lung tumor development and presentation.

A 53-year-old African American female with a history of tobacco, marijuana, and cocaine use presented in 2010 with vasculitic skin lesions of her lower extremities. This was later confirmed as LV via biopsy showing similar results as displayed in Figure 4. A drug screen was positive for levamisole-adulterated cocaine. Multiple visits for LV followed, as shown in Figure 3 . Each workup had been nondiagnostic for a systemic vasculitis with negative ANA, ANCA, complement, dsDNA, and cryoglobulins. In 2014 she was diagnosed with hepatitis C and was required to halt cocaine use for the course of her 10-week treatment. After treatment, she presented again with ecchymotic tender macules on the ears, nose, cheeks, breasts, abdomen, and extremities for which she was hospitalized 18 days.

Due to the severity of her condition during her hospital stay, she was sedated and intubated for 10 days. Empiric antibiotic therapy was initiated with vancomycin and piperacillin/ tazobactam. Cultures of the leg lesions grew MRSA and P. aeruginosa. Another extensive workup for vasculitis showed negative cryoglobulins, ANA, C3 & C4 complement, and AntiSSA and AntiSSB antibodies. Other lab values are shown below in Table1 .

ESR

Protein S

53

33%

RF

pANCA

36 H

1:640

Protein C 53% L

MPO

34.5

Table 1. Lab values

A chest XR showed no abnormalities. The patient received IV heparin and was started on high dose steroids, bactrim and ciprofloxacin for 14 days. Her wounds were monitored outpatient. The patient had another 2 LV episodes due to cocaine adulterated with levamisole in January and March of 2016, both requiring hospitalization. She again received treatment with prednisone, and IV heparin. Additional treatment included low frequency ultrasound treatments to the wounds, cefazolin for infections, split-thickness skin graft (STSG) to three of her larger open areas, and tendon release at her L popliteal fossa to mitigate contracture formation were also attempted.

Figure 1. Timeline of disease

Figure 4. Leukocytoclastic vasculitis biopsy result: A dermal small vessel showing a neutrophilic-rich infiltrate with karyorrhexis and extravasated erythrocytes within the vessel wall and adjacent tissue. Intraluminal fibrin thrombi are also present.

Figure 3. Course of care for recurring leukocytoclastic vasculitis

Notably, all of her chest imaging during these admissions were negative for any nodules, infiltrates, or adenopathy. After discharge, the patient stayed clean from drug use, had no further episodes of LV, and her skin ulcers healed well. She returned in June of 2018 presenting with progressively worsening shortness of breath and an overall 60 lb. unintentional weight loss. Imaging showed a large right upper lung mass with paratracheal and mediastinal adenopathy. The mass was confirmed to be a small cell neuroendocrine carcinoma with no metastases. Induction of treatment was with carboplatin/VP-16; followed by concurrent chemotherapy and radiation in September 2018. She had a brief remission, but relapsed and was trialed on nivolumab. The patient’s condition quickly worsened, and she unfortunately died February 2020.

References

Figure 1 & 2. Leukocytoclastic vasculitis in an African American female.

1. Arora, N.P., Jain, T., Bhanot, R. et al. Levamisole-induced LV and neutropenia in a patient with cocaine use: An extensive case with necrosis of skin, soft tissue, and cartilage. Addict Sci Clin Pract 7, 19 (2012). https://doi.org/10.1186/1940-0640-7-19 2. Belfonte CD, Shanmugam VK, Kieffer N, Coker S, Boucree S, Kerr G. Levamisole-induced occlusive necrotising vasculitis in cocaine abusers: an unusual cause of skin necrosis and neutropenia. Int Wound J . 2013;10(5):590-596. doi:10.1111/j.1742 481X.2012.01027.x 3. Lee KC, Ladizinski B, Federman DG. Complications associated with use of levamisole-contaminated cocaine: an emerging public health challenge. Mayo Clin Proc . 2012;87(6):581-586. doi:10.1016/j.mayocp.2012.03.010

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