Published online August 14, 2006
PEDIATRICS Vol. 118 No. 3 September 2006, pp. e921-e923 (doi:10.1542/peds.2006-0487)

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EXPERIENCE & REASON

Combined Treatment of Steroids and Cyclosporine in Kimura Disease

Satoshi Sato, MD, PhD, Hisashi Kawashima, MD, PhD, Shinji Kuboshima, MD, PhD, Kiyoko Watanabe, MD, PhD, Yasuyo Kashiwagi, MD, PhD, Kouji Takekuma, MD, PhD and Akinori Hoshika, MD, PhD

Department of Pediatrics, Tokyo Medical University, Tokyo, Japan

ABSTRACT

Kimura disease is a rare but distinctive chronic eosinophilic inflammatory disorder that is characterized by tumor-like lesions in the soft tissue and lymph nodes of the head and neck or parotid gland. Recently, many immunopathogenetic features of underlying T lymphocytes and related cytokines have been noted in Kimura disease. However, few previous studies have investigated the serial levels of cytokines in children. In this report we describe an 11-year-old Japanese boy with relapsing Kimura disease. Before the diagnosis of Kimura disease, the patient had a swelling on his left neck. Steroids were effective, but the tumor relapsed within a few months as the steroids were tapered. He was treated with steroids and cyclosporine. This treatment was done by measuring serial levels of serum soluble interleukin-2 receptor, interleukin-4, interleukin-5, and eosinophil cationic protein. These results suggest the activation of T-helper cells and T-helper 2 cytokines, that after activated B cells and eosinophilic infiltration play an important role in Kimura disease, and that cyclosporine suppresses the activity of this disease.

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Key Words: Kimura disease • cyclosporine • interleukin • Th2 • eosinophils

Abbreviations: Ig, immunoglobulin • IL, interleukin • mRNA, messenger RNA • Th2, T-helper 2 • sIL-2R, soluble interleukin 2 receptor • ECP, eosinophil cationic protein

Kimura disease is an eosinophilic inflammatory disorder characterized by tumors in the head and neck region.¹ Increased peripheral blood eosinophil counts and serum immunoglobulin E (IgE) are common. Although its etiology is not well understood, the clinical and histopathological features are consistent with features of allergic or autoimmune disease. The expression of interleukin 4 (IL-4), IL-5, and IL-13 messenger RNA (mRNA) is elevated in peripheral blood mononuclear cells in patients with Kimura disease, suggesting that these T-helper 2 cytokines play a part in the dysregulation of eosinophil dynamics and IgE synthesis.² Our report describes successful treatment of an 11-year-old Japanese boy with steroids and cyclosporine and serum soluble interleukin 2 receptor (sIL-2R), IL-4, IL-5, and eosinophil cationic protein (ECP).

CASE REPORT

An 11-year-old Japanese boy presented with cervical lymphadenopathy. The mass appeared 4 years earlier. There were no systemic symptoms (pain, fever, night sweats, or weight loss). He had been treated with steroids several times in the past 4 years. The masses showed regression, but recurrence occurred when the dose was tapered to 20 mg/day. The patient was admitted to the Tokyo Medical University Hospital on September 28, 2005, for diagnosis and treatment. He had a past history of bronchial asthma and atopic dermatitis. A nontender, nonfluctuant, firm mass measuring 5 x 8 cm was palpable on the left side of his neck. Laboratory data included a hemoglobin level of 13.8 g/dL, platelet count of 320 x 10⁹/L, and white cell count of 21.4 x 10⁹/L; the differential showed 47% eosinophils, 35.6% segmented neutrophils, 13.3% lymphocytes, and 3.9% monocytes. The erythrocyte sedimentation rate was 60 mm/hour. The results of C-reactive protein and serum electrolyte testing, liver-function tests, and albumin, serum urea nitrogen, and creatinine testing were normal. Analysis of the urine showed no abnormal values. Computed tomography of his head and neck showed a heterogeneous enhancing mass and multiple lymph nodes (Fig 1). IgE was elevated at 15446 IU/mL (reference range: <250 IU/mL), with IgG, IgM, and IgA within normal limits. The serum IL-4, IL-5, and ECP levels had increased to 36.5 pg/mL (reference range: <6.0 pg/mL), 64.5 pg/mL (reference range: <10 pg/mL), and 104 µg/L (reference range: <14.7 µg/L), respectively. The serum sIL-2R level was elevated to 1230 U/mL (reference range: 220–530 U/mL). On the other hand, his serum IL-6 (reference range: <4.0 pg/mL) and interferon (reference range: <0.1 IU/mL) levels continued in the reference range throughout the clinical course.

View larger version (86K): [in this window] [in a new window]   FIGURE 1 Computed tomograph showing a heterogeneous enhancing mass (arrow 1) and multiple lymph nodes (arrow 2).

 
Histologic examination of a biopsy sample from the left side of the neck showed a proliferation of lymphoid follicles and abundant infiltrate of eosinophils. There was no evidence of malignant change. The histopathologic and clinical findings suggested Kimura disease (Fig 2).

View larger version (179K): [in this window] [in a new window]   FIGURE 2 A biopsy sample taken from the left cervical mass showing follicular lymphoid with diffuse eosinophilic infiltration (hematoxylin and eosin, x200).

 
On October 18, 2005, we began treatment with prednisolone and cyclosporine at initial doses of 40 mg/day and 4 mg/kg per day, respectively, and 7 days later eosinophilia had improved. The dose of prednisolone was then gradually reduced, and the nodular lesion had almost cleared. The trough blood concentration of cyclosporine was <100 ng/mL.

After the start of oral prednisolone and cyclosporine, eosinophilia and levels of serum sIL-2R, IL-5, and ECP had improved. Total serum IgE and IL-4 levels decreased gradually (Fig 3). The laboratory data were stable with 5 mg of prednisolone on alternate days and 4 mg/kg per day of cyclosporine therapy.

View larger version (21K): [in this window] [in a new window]   FIGURE 3 Laboratory data (IgE, sIL-2R, IL-4, IL-5, and ECP) of the patient with Kimura disease during the treatment.

 

DISCUSSION

Kimura disease is an uncommon, chronic inflammatory skin disease that usually occurs in the head and neck¹ and became recognized worldwide. The disease occurs predominantly in Asian males.³ The clinical course of Kimura disease is often complicated by nephritic syndrome.⁴ The disease is also associated with eosinophilia and elevated serum IgE levels. Katagiri et al² reported a finding of elevated mRNA levels of IL-4, IL-5, and IL-13 in patients with Kimura disease. The role of cytokines, especially IL-4, IL-5, and IL-13, has been a focus of attention in the regulation of IgE production by B cells required for Th2 lymphocyte differentiation.⁵ IL-5 is a major cytokine for mature eosinophil activation and accelerates differentiation, proliferation, and chemotaxis.⁶ Kimura et al⁷ reported a finding of elevated eotaxin and RANTES (regulated on activation, normal T-cell expressed and secreted) expression in mast cells and T cells with Kimura disease. Also, Blanchard et al⁸ have explained that eotaxin-3 production by Th2 cytokine-stimulated cells can lead to infiltrate of eosinophils in eosinophilic esophagitis. Chemokines such as eotaxin may play an important role in inducing local eosinophilic infiltration into sites of inflammation in Kimura disease. Thus, these data suggest that patients whose Th2 cytokine pathway is prone to activation by unknown antigens might present with Kimura disease. Tsukadaira et al⁹ described an elevated sIL-2R, granulocyte/macrophage colony-stimulating factor, and tumor necrosis factor in peripheral blood. sIL-2R is known to be the IL-2 receptor chain release from activated T or B lymphocytes. Kimura disease may be a disease in which activated T lymphocytes release cytokines and cause eosinophil activation.

There are few reports about treatment with cyclosporine for Kimura disease. Cyclosporine acts on intracellular binding proteins and inhibits calcium-dependent signaling pathways involved in transcription of the IL-2 gene. Reduced IL-2 synthesis results in inhibition of T-lymphocyte proliferation and attenuation of the immune response. Katagiri et al² explained that mRNA levels of cytokines and eosinophils were suppressed when the blood concentration of cyclosporine was >75 ng/mL in an adult patient with Kimura disease. There have also been reports of children with Kimura disease who were treated with steroids and immunosuppressive agents such as cyclosporine.¹⁰ In our case, peripheral eosinophil counts and ECP levels decreased immediately after the commencing of steroid and cyclosporine therapy and were maintained within the reference range. Serum sIL-2R, IL-4, and IL-5 decreased slowly. During treatment, the IgE level showed a gradual decrease below 5000 IU/mL, and the tumor did not relapse until 4 months later. It is proposed that cyclosporine affects Th2 cells. We have concluded that activated Th2 cells could be a major factor in the development of Kimura disease, because the number of peripheral eosinophils decreased in association with decreases in levels of serum sIL-2R, IL-4, IL-5, ECP, and IgE during steroid and cyclosporine therapy.

Two other major therapeutic options for Kimura disease, surgical resection and irradiation, are thought to be insufficient. Regrowth appears after surgical resection,¹¹ and irradiation is not advocated for young patients.¹²

CONCLUSIONS

This case demonstrates that activated T lymphocytes may play important roles in the immunopathogenesis of Kimura disease through the increased presence of sIL-2R and Th2 cytokines (IL-4 and IL-5). We recommend a combined therapy of steroids and cyclosporine to suppress Kimura-disease activity.

FOOTNOTES

Accepted Mar 20, 2006.

Address correspondence to Satoshi Sato, MD, PhD, Department of Pediatrics, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. E-mail: sato115{at}tokyo-med.ac.jp

The authors have indicated they have no financial relationships relevant to this article to disclose.

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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics

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