|CASE BASED REVIEW
|Year : 2021 | Volume
| Issue : 3 | Page : 353-358
Levamisole-Induced immune phenomenon and its various clinical manifestations in children: Two case reports along with review of literature
Anu Punnen Kocheril1, T Sathish Kumar1, Dharshini Sathishkumar2
1 Department of Pediatrics, Pediatric Rheumatology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Dermatology, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||24-Dec-2020|
|Date of Acceptance||31-Mar-2021|
|Date of Web Publication||21-Sep-2021|
Dr. Anu Punnen Kocheril
Department of Pediatrics, Pediatric Rheumatology, Christian Medical College, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
In literature, levamisole-induced immune manifestations were described mostly in association with its use in treatment of rheumatoid arthritis, malignancies, and recently, in relation to the use of illicit cocaine contaminated with levamisole among adults. Even though levamisole has been proven to be an inexpensive, safer, and effective drug with minimal side effects among children, it is not possible to undermine its potential side effects. The objective of this study was to describe levamisole-induced immune phenomenon and its manifestation in children. We describe two children with levamisole-induced immune phenomenon, leading to limb ischemia resulting in a gangrene and autoamputation of toes in the first child and an isolated microscopic hematuria in the second child along with a thorough review of available knowledge on this rare manifestation in children. Increased awareness of these rare but severe manifestations will remind clinicians to keep a high index of suspicion, its early recognizing, and withdrawal of offending drug before severe morbidity occurs in those children on levamisole.
Keywords: Antineutrophil cytoplasmic antibody-associated vasculitis, drug-induced vasculitis, levamisole-induced vasculitis, vasculopathy
|How to cite this article:|
Kocheril AP, Kumar T S, Sathishkumar D. Levamisole-Induced immune phenomenon and its various clinical manifestations in children: Two case reports along with review of literature. Indian J Rheumatol 2021;16:353-8
|How to cite this URL:|
Kocheril AP, Kumar T S, Sathishkumar D. Levamisole-Induced immune phenomenon and its various clinical manifestations in children: Two case reports along with review of literature. Indian J Rheumatol [serial online] 2021 [cited 2021 Dec 6];16:353-8. Available from: https://www.indianjrheumatol.com/text.asp?2021/16/3/353/324122
Levamisole is a synthetic imidazothiazole derivative, historically used primarily as an anthelminthic in veterinary practice and in humans. In the 1970s, levamisole was used as an immunomodulatory drug in the treatment of various cancers and rheumatoid arthritis. Subsequently, it was studied and used in numerous autoimmune conditions such as systemic lupus erythematosus (SLE), dermatomyositis, scleroderma, inflammatory skin diseases, vitiligo, and inflammatory bowel disease. Levamisole was banned in the United States in 1999 because of the adverse side effects such as agranulocytosis, leukopenia, and vasculitis. Around late 2009, multiple vasculitic manifestations surfaced in cocaine users which were later found to be due to levamisole adulteration in cocaine.
Immune manifestation associated with levamisole resulting in a spectrum of clinical presentations has been described in literature since the 1970s. We came across various terminologies in relation to this immune phenomenon in literature, describing mild-to-severe forms, mostly in adult populations such as levamisole-induced vasculitis (LIV), levamisole-induced vasculopathy, levamisole-induced necrotic skin syndrome, cocaine/levamisole-associated autoimmune syndrome, levamisole-contaminated cocaine-induced vasculitis, drug-induced vasculitis, and disseminated autoimmune disease/systemic involvement. The clinical profile and laboratory features can be misleading and challenging for an accurate diagnosis as it overlaps to a significant degree with the primary form of autoimmune diseases. Current knowledge about this autoimmune syndrome associated with levamisole in children is very limited.
Levamisole has been considered the least toxic steroid-sparing drug for preventing relapse of steroid-sensitive nephrotic syndrome. Mühlig et al. had summarized various observational studies, randomized control trials, and meta-analyses on the usefulness of the drug in nephrotic syndrome, and in most of the studies, the safety profile was reassuring. We describe two children with levamisole-induced immune manifestation on its therapeutic dose, with literature search of similar cases. In view of these rare but potentially serious manifestations, clinicians should be aware of this entity for early diagnosis and intervention.
| Methodology|| |
We performed a review of records of children <18 years with levamisole-induced immune manifestation at a tertiary center in South India. Informed consent was taken from parents. The study was approved by the Institutional Review Board of Christian Medical College, Vellore, India. Search of previously documented similar cases in children was conducted using several databases including PubMed, EMBASE, Scopus, and Web of Science from 1970 to 2020. The search results included all publications in the English language. Search terms included levamisole induced vasculitis/vasculopathy, autoimmunity, antineutrophil cytoplasmic antibody (ANCA)-related vasculitis, drug-induced vasculitis as a text word, and controlled vocabulary. The authors confirm that the data supporting the findings of this study are available within the article. As per our institutional policy, 3 or more cases as a case series needs IEC clearance ,hence clearance was not taken from IEC. But consent was taken from both parents as per institutional rules.
A 5½-year-old boy with infrequently relapsing nephrotic syndrome on levamisole (50 mg on alternate days) presented with intermittent fever and bilateral foot pain for the past 2 weeks. On evaluation, he had pancytopenia and hepatosplenomegaly. Bone marrow examination ruled out malignancy. Two days later, he had swelling and bluish discoloration of the left foot toes [Figure 1]a. The bluish discoloration extended till the left midfoot within hours [Figure 1]b. There were purpuric rashes over the ears, right lower limb, and right gluteal area. All central and peripheral pulses were well felt. Hemoglobin was 7.9 g/dl; total leukocyte count was 3.5 × 109/L with a differential count of N19%, L62%, M17%, and E2%; and platelet count was 0.72 × 109/L. Erythrocyte sedimentation rate (70 mm/1 h) and C-reactive protein (156 mg/L) were elevated. Urine microscopy showed mild proteinuria (Urine protein/creatinine ratio (UP/UC) - 0.96). Acute limb ischemia secondary to underlying vasculitis or procoagulant state was considered. Emergency arterial and venous Doppler ruled out thrombosis of lower limbs. Anti-proteinase 3 (anti-PR3) (71 U/mL) and anti-myeloperoxidase (anti-MPO) (26 U/mL) antibodies were positive, with a moderately positive lupus anticoagulant (LAC) and a negative antinuclear antibody (ANA), normal C3 and C4, and a negative sickle cell preparation. Computed tomography (CT) angiogram of both lower limbs revealed narrowing of the anterior and posterior tibial and dorsalis pedis arteries on the left side compared to the right side. Hence, a diagnosis of levamisole-induced autoimmunity with vasculopathy and systemic involvement was considered. Levamisole was stopped. He was initiated on intravenous pulse injections of methylprednisolone (600 mg/day for 5 consecutive days), aspirin, and therapeutic anticoagulation with unfractionated heparin. There was no further extension of the gangrene. Warfarin was added later after stopping heparin. The cytopenias recovered within 2 weeks of stopping levamisole. Complete thrombotic workup after 6 weeks was negative. Repeated parameters of antiphospholipid antibodies (aPLs), anti-PR3, and anti-MPO antibodies were negative after 12 weeks. His hepatosplenomegaly resolved within 6 months. Subsequently, on follow-up, he had autoamputation of all the left foot toes [Figure 1]c and [Figure 1]d. He was followed up in the outpatient department on tapering doses of prednisolone (over 6 months) and warfarin and aspirin for 12 months.
|Figure 1: Acute limb ischemia, subsequently leading to gangrene and autoamputation of toes (a) at presentation, (b) after 12 h, (c) after 1 month, (d) after 6 months|
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A 9-year-old girl was on levamisole 50 mg once daily for vitiligo (over the face) for the past 2 years. She was evaluated for a recent onset of swelling and pain of multiple joints for the past 1 month and in view of her clinical symptoms, positive ANA and LAC with persistent microscopic hematuria, SLE was considered and renal biopsy was advised. Hence, she was referred to our institute. Her general and systemic examination was normal with normal blood pressures. Her urine persisted to show microscopic hematuria (60 red blood cells/hpf). Blood investigation showed a positive ANA and LAC with a normal C3 and C4 and negative anti-double-stranded DNA (anti-dsDNA) antibody. Anti-PR3 was negative, but anti-MPO was very high (>200 U/mL). Ultrasonography of the abdomen was normal. Renal biopsy was reported as normal. Hence, levamisole-induced autoimmunity with arthritis and isolated hematuria was considered. She was kept under follow-up after advising to stop levamisole. Subsequently, microscopic hematuria subsided by 3 months of follow-up. ANA and LAC were also negative by 3 months. Anti-MPO antibody became negative by 6 months.
The baseline demographic features and investigations are shown in [Table 1].
| Discussion|| |
We report two children with “levamisole-induced immune phenomenon” resulting in its vivid and unique manifestations. The classical spectrum involves, typical skin lesion with vasculopathy/vasculitis on skin biopsy, fever, arthralgia/arthritis, leukopenia(especially neutropenia) and associated multiple circulating autoantibodies. The typical skin lesion described is a tender, purpuric rash in a retiform or stellate pattern with or without central necrosis involving the extremities, trunk, nasal tip, digits, cheek, and ears. A suspicion about drug-induced immune phenomenon than the primary autoimmune disorder should arise, when several antibodies rather than a significant titer of specific antibody are found during evaluation.
Among levamisole-induced immune spectrum, the first case of cutaneous vasculitis was reported in 1978 in a case of rheumatoid arthritis treated with levamisole. The first case report in children was described by Laux-End et al in 1996. Rongioletti et al in 1999 reported similar levamisole-induced manifestations in four children with frequently relapsing nephrotic syndrome. Most retrospective studies reported either no side effects or only minor reversible side effects such as rash, fever, abdominal pain, neutropenia, thrombocytopenia, or elevated liver enzymes which disappear on cessation of levamisole. Severe manifestations were reported more in adults than children which included agranulocytosis, extensive skin necrosis, acute coronary syndrome, and pulmonary hypertension.
The pathophysiology of this immune phenomenon associated with levamisole in children is still poorly understood. Newer studies explain about new environmentally related factors (epigenetics), the genetic predisposition, and a new form of cell death called NETosis, which provides unique exposure of enzymes to the immune system leading to autoimmunity. NETs (neutrophil extracellular traps) consisted of a scaffold of chromatin DNA intermingled with histone and constituents of cytoplasmic polymorphonuclear cell (PMN) granules, including MPO, PR3, and human neutrophil elastase. In a current study, levamisole was found to increase NET formation (NETosis) through muscarinic M3 subtype receptors which was toxic to endothelial cells causing impaired vasorelaxation. Along with levamisole, hydralazine, propylthiouracil, cocaine, and D-penicillamine are also reported to causes vasculitis with circulating autoantibodies.
We could identify a total of 12 pediatric cases (including index cases) associated with levamisole-induced immune manifestation in literature [Table 2]. Among these cases, eight were boys and four were girls. The mean age at presentation was 9.6 ± 2.9 years (mean ± standard deviation), age ranging from 5 to 16 years. Most were children treated for frequently relapsing nephrotic syndrome on therapeutic dose of levamisole. It was interesting to note that these manifests were more pronounced in older age groups than the younger groups. Majority of children (83%) had a cutaneous manifestation of purpura over the ear, cheeks, and extremities. Two children had a bullous hemorrhagic lesion over the ear, and two did not have skin lesions. Other symptoms were necrotic skin lesions, arthralgia, fever, microscopic hematuria, proteinuria, and gangrene. Three children were reported to have presented with severe systemic symptoms, with fever, cytopenias (especially anemia and leukoneutropenia), and hepatosplenomegaly. The laboratory parameters which were more pronounced was ANCA positivity (92%)(especially p-ANCA), aPLs positivity (50%) (mostly LAC) and ANA positivity (33%). Other serological abnormalities described were anti-histone and anti-dsDNA positivity and low C3. Almost all cases had multiple serological antibody positivity. Skin biopsies showed leukocytoclastic vasculitis/thrombotic vasculopathy. Levamisole was consumed in its therapeutic dosage (2–2.5 mg/kg alternate day), and the mean duration before starting of symptoms was 1.5–2 years (longest was 60 months). Antibodies disappeared by a mean duration of 6 months in majority of cases.
|Table 2: Review of similar cases in literature with levamisole-induced autoimmune phenomenon and its manifestations|
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Our first child was on levamisole for 1½ years for frequently relapsing nephrotic syndrome and presented with systemic involvement with acute limb ischemia leading to gangrene of the lower limb. We are reporting the first case report of this type of presentation associated with levamisole-induced immune manifestations in literature. A case of profound acute limb ischemia with gangrene was reported in an adult associated with consumption of cocaine in 2015. After stopping the drug, all his clinical symptoms, laboratory parameters, and serological abnormalities improved gradually. Our second child was on levamisole for the past 2 years for vitiligo, and she presented with isolated hematuria with various serological abnormalities typical of levamisole-induced autoimmunity. Thalgahagoda et al. reported a case of pauci-immune glomerulonephritis associated with levamisole in a 12-year-old female child.
There are no clear-cut protocols or guidelines defining ideal treatment for levamisole-induced autoimmune phenomenon and its manifestations. The mainstay of therapy is withdrawal of the offending drug. In all the reported cases including ours, significant improvement of all symptoms and laboratory parameters was seen after stopping levamisole. Management mostly depends on the severity of involvement, systemic features, and end-organ damage associated with it, where corticosteroids might have a role. Plasmapheresis was tried in few cases. Most of the children had mild symptoms, which regress with stopping the drug. Our first child was treated with pulse methylprednisolone followed by oral prednisolone, and anticoagulants along with supportive measures. Progression of the gangrene stopped. He was rehabilitated under exercise and prosthetic training program and doing very well on follow-up. In the second child, isolated hematuria resolved in 3 months after stopping the drug.
| Conclusion|| |
Most cases of levamisole-induced autoimmune phenomenon were seen in older children, which warrant close follow-up in these age groups while on this drug. Children present with typical skin involvement and leukoneutropenia, ANA, ANCAs, and/or aPLs. There should be a close watch for severe manifestations. It is very crucial to be aware about this entity, as early recognition, stopping levamisole, and initiation of treatment will be the key strategy to avoid morbid sequelae.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient/parents consent forms. In the form the parent (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]