Clinical Pediatric Hematology-Oncology Volume 24ㆍNumber 2ㆍOctober 2017 CASE REPORT

스테로이드의존 재발성 기쿠치병에서 Hydroxychloroquine의 치료효과

장경미ㆍ이재민

영남대학교 의과대학 소아과학교실

A Case of Recurrent Steroid-dependent Kikuchi–Fujimoto Disease Successfully Treated with Hydroxychloroquine

Kyung Mi Jang, M.D. and Jae Min Lee, M.D. Department of Pediatrics, Yeungnam University College of Medicine, Daegu, Korea

Kikuchi–Fujimoto disease (KFD) is known as a self-limiting disease. The most common pISSN 2233-5250 / eISSN 2233-4580 symptoms include , cervical , and pain, but nonspecific symptoms https://doi.org/10.15264/cpho.2017.24.2.144 Clin Pediatr Hematol Oncol such as joint pain, nausea, chills, diaphoresis, and diarrhea may also be present. Its 2017;24:144∼147 clinical course is generally benign, and symptoms including fever disappear within sev- eral months without special treatment. Thus, there is no specific recommended treatment Received on August 24, 2017 for patients with KFD. However, some patients suffer from prolonged fever or systemic Revised on September 11, 2017 symptoms such as , skin rash, arthralgia, and aseptic . Many stud- Accepted on October 9, 2017 ies have reported the effectiveness of in patients with prolonged fever and systemic symptoms. Our patient also responded favorably to steroids; however, the Corresponding Author: Jae Min Lee disease relapsed while tapering. Recently, some studies reported the effectiveness of hy- Department of Pediatrics, droxychloroquine (HC) in patients with KFD. Herein, we report successful treatment with Yeungnam University College of HC in an adolescent patient with recurrent KFD dependent on steroids without any Medicine, 170 Hyeonchung-ro, symptoms of . Nam-gu, Daegu 42415, Korea Tel: +82-53-620-3536 Fax: +82-53-629-2252 Key Words: Kikuchi–Fujimoto disease, Histiocytic necrotizing lymphadenitis, Hydroxy- E-mail: [email protected] chloroquine, Children, Lymphadenopathy ORCID ID: orcid.org/0000-0001-6822-1051

for KFD, and antipyretics and non-steroidal anti-inflam- Introduction matory drugs (NSAIDs) are usually administered to relieve symptoms. Herein, we present a relapsing case of a Kikuchi–Fujimoto disease (KFD), also known as histio- 17-year-old adolescent patient diagnosed with KFD, despite cytic necrotizing lymphadenitis, is characterized by cervical NSAID and treatments, and successful treat- lymphadenopathy and prolonged fever. KFD is known to ment with hydroxychloroquine (HC). be a self-limiting disease with low recurrence rates [1]. Diagnosis of KFD is confirmed with histopathologic exami- Case Report nation by biopsy [2]. Symptoms including fever generally disappear within several months without special An otherwise healthy 17-year-old boy with prolonged fe- treatment. Therefore, there are no special recommendations ver, myalgia, and was admitted to our hospital.

144 KFD Successfully Treated with Hydroxychloroquine

He was suspected with bacterial lymphadenitis and was formed on the first day of hospitalization. treated with antibiotics for 11 days. The fever lasted for 11 He was empirically treated with intravenous antibiotics days despite antibiotic administration during the inpatient (amoxicillin-clavulanate, ceftriaxone, clindamycin) until ac- stay and local medical center visit. He presented no history quiring the results of biopsy, and his fever continued to of recent overseas travel, medication, or contact with sick spike ＞39.5oC for 5 days. Biopsy results indicated histio- people. Upon physical examination, he exhibited painful cytic necrotizing lymphadenitis, which confirmed KFD (Fig. lymph node enlargement (2.0×2.0 cm) located inferior to 2). Methylprednisolone (0.86 mg/kg/day, 60 mg/day) was the left mandible, and his body temperature was 38.2oC. administered intravenously to the patient for 5 consecutive Other physical examinations, including those of the axillary days, and he stopped receiving antibiotics. and inguinal lymph nodes, were unremarkable. Laboratory He became afebrile and other symptoms such as myalgia findings were as follows: white blood cell (WBC) count, and sore throat disappeared. After discharge, he was treat- 4,140/L (53.5% ); hemoglobin level (Hb), 13.9 ed with oral prednisolone at (1 mg/kg/day, 60 mg) for 4 g/dL; and platelet count, 213,000/L. Kidney and liver days and NSAID, and lymphadenopathy resolved; the dos- function test results were unremarkable. Other laboratory age was then reduced to (0.5 mg/kg/day, 30 mg) for 4 days findings were as follows: C-reactive protein (CRP) level, and both oral prednisolone and NSAID discontinued. 0.974 mg/dL (normal range: ＜0.5 mg/dL); erythrocyte Thirteen days after ceasing medications, his fever devel- sediment rate (ESR), 48 mm/h (normal range: 0-20 mm/h); oped again with tender in the C3 level, 165 mg/dL (normal range: 83-177 mg/dL); C4 lev- same lesion. He was re-admitted and at that time laboratory el, 54 mg/dL (normal range: 15-45 mg/dL); CH50 level, 80 findings were as follows: WBC count, 1,840/L (50.6% neu- U/mL (normal range: 75-160 U/mL); antinuclear antibody trophils); Hb level, 14.7 g/dL; platelet count, 185,000/L; (ANA), negative; cytomegalovirus IgM, negative; and CRP level, 1.95 mg/dL (normal range: ＜0.5 mg/dL); and Epstein–Barr virus IgM and polymerase chain reaction ESR level, 34 mm/h (normal range: 0-20 mm/h). Kidney (PCR), negative. Lymph node enlargement with slightly ne- and liver function test results were unremarkable. The pa- crotic lesions were detected (level IIA) on neck computed tient was treated with intravenous methylprednisolone tomography scan (Fig. 1). Core needle biopsy was per- (0.86 mg/kg/day, 60 mg/day) and NSAID for 3 consecutive

Fig. 2. Lymph node biopsy shows numerous and variable numbers of immunoblasts with karyorrhectic bodies. Fig. 1. About 20 mm sized enlarged lymph node with slightly Plasma cells and neutrophils are absent. Magnification: ×200 necrotic lesion was seen in left level IIA (arrow). (hematoxylin and eosin).

Clin Pediatr Hematol Oncol 145 Kyung Mi Jang and Jae Min Lee days; his fever subsided and symptoms like cervical lym- patients in Korea [10]. However, Hyun et al. explained that phadenopathy, myalgia, and headache improved. Upon the high recurrence rate may have been due to selection discharge, he was symptom-free; thus, oral prednisolone bias because the study was from a Kikuchi center of the was tapered by half at weekly intervals and NSAID admin- tertiary hospital in which patients present with more severe istration was continued. About three weeks after discharge, symptoms and higher recurrence rates [11]. Although re- symptoms recurred at a dosage of 5 mg/day and the dosage currence of KFD is possible, clinical differential diagnoses was then increased to 20 mg/day. His fever subsided, but including infectious mononucleosis, mycobacterium tuber- lymph node enlargement did not resolve. We switched culosis, systemic erythematosus (SLE), bacterial lym- NSAID used for two months to HC (3.0 mg/kg/day, 200 phadenitis, Kawasaki disease, and malignancy should be mg), decreased the dosage of oral prednisolone by half at considered. weekly intervals, and eventually discontinued prednisolone KFD is usually considered to be self-limiting; it is also treatment after 7 weeks. Treatment was continued with HC resolved within 4 months [1]. Therefore, most reports rec- alone, which was tapered by half at intervals of 2 weeks ommend no special treatment. However, KFD exhibits a and discontinued after 6 weeks of medication. He con- wide spectrum of clinical manifestations [4]. Many patients tinues to be monitored regularly, and remains healthy with- suffer from prolonged fever or systemic symptoms such as out any symptoms 10 months later. splenomegaly, skin rash, arthralgia, and aseptic meningitis. Furthermore, Uslu et al. have reported that KFD may be Discussion complicated with lethal outcomes, such as pulmonary hem- orrhage and disseminated intravascular coagulopathy [12]. KFD usually develops in young adults under the age of There are many studies focused on the effectiveness of cor- 30 years and is confirmed by biopsy with histological find- ticosteroids and their mechanism to lower the production ings of histiocytic necrotizing lymphadenitis [3]. KFD dis- of cytokines derived from histiocytes [13]. Thus, administer- plays a high prevalence in Asian populations; particularly ing corticosteroids is reasonable to treat KFD, but proper in Far East nations including Korea, there are a few KFD dosages and durations of treatment are still controversial. cases reported in children [3-5]. The etiology of KFD is un- Kang et al. recommend that corticosteroids should be con- known, although genetic, viral, and autoimmune hypoth- sidered in patients with high-grade fever, leukopenia, more eses have been proposed [3,6]. Serum concentrations of in- systemic symptoms, and larger lymph nodes [4]. In this flammatory cytokines like interleukin-6 (IL-6), interferon-, study, oral corticosteroids at initial doses (0.5-1.5 mg/kg) and Fas ligands are elevated during the acute phase in pa- are administered and are then tapered. tients with KFD [7,8]. These findings suggest that the activa- HC is generally used as an immune modulator, to induce tion of histiocytes are triggered by a viral infection to pro- apoptosis and lymphoid accumulation, and to suppress the duce excessive inflammatory cytokines. Such excessive cy- production of inflammatory cytokines like IL-1 and IL-6. HC tokines may not only cause the symptoms of KFD, but also has been used widely in diverse disease as well as rheuma- activate more histiocytes; a vicious cycle is formed, and fe- toid and systemic lupus erythematosus. Lately there ver may then prolong [9]. Hemophagocytic lymphohistiocy- is randomized trial of HC for chronic graft-versus-host dis- tosis (HLH) is characterized by the reactivation of phag- ease in children [14]. HC prevents autophagy and leads to ocytic histiocytes that are stimulated by T cells. The clin- apoptosis of effector T cells, which may induce auto- icopathological features of HLH are similar to those of KFD; immunity. Moreover, HC alkalifies intracellular vesicles and some patients with KFD progress to HLH, and this is not prevents the growth of bacteria and viruses. These are rea- surprising. sons to promote the use of HC. A previous study demon- Its recurrence rate is known to be low (3-4%) [1]. Song strated that the use of HC with steroids is effective in pa- et al. reported a high recurrence rate (20.5%) among adult tients with autoimmune diseases including SLE. There are

146 Vol. 24, No. 2, October 2017 KFD Successfully Treated with Hydroxychloroquine also recent reports on the effectiveness of HC in patients 4. Lee KY, Yeon YH, Lee BC. Kikuchi-Fujimoto disease with with KFD without autoimmune disease [11]. HC has few prolonged fever in children. Pediatrics 2004;114:e752-6. 5. Rakesh P, Alex RG, Varghese GM, et al. Kikuchi-fujimoto dis- systemic side effects, however, HC can develop irreversible ease: clinical and laboratory characteristics and outcome. J retinal toxicity. This risk is associated with dosage and du- Glob Infect Dis 2014;6:147-50. ration of use. Ronald et al. reported that daily use of 5.0 6. Deaver D, Horna P, Cualing H, Sokol L. Pathogenesis, diag- mg/kg of ideal body weight or less had a low risk for up nosis, and management of Kikuchi-Fujimoto disease. Cancer Control 2014;21:313-21. to 10 years of use [15]. Therefore, the regular monitoring 7. Kato K, Ohshima K, Anzai K, Suzumiya J, Kikuchi M. Elevated is needed at high dosages and long duration of use. serum-soluble Fas ligand in histiocytic necrotizing lympha- Our patient did not present with any symptoms of SLE, denitis. Int J Hematol 2001;73:84-6. including laboratory test findings of antinuclear antibodies, 8. Kubota M, Tsukamoto R, Kurokawa K, Imai T, Furusho K. Elevated serum interferon gamma and interleukin-6 in patients C3, C4, or CH50. However, he was dependent on steroids; with necrotizing lymphadenitis (Kikuchi's disease). Br J the disease relapsed while tapering steroid doses. By ad- Haematol 1996;95:613-5. ministering HC, we could taper off the steroid, and finally 9. Facchetti F, Vermi W, Mason D, Colonna M. The plasmacytoid also cease HC treatment. If a patient with KFD presents monocyte/interferon producing cells. Virchows Arch 2003; 443:703-17. with autoimmune disease or side effects such as a cush- 10. Song JY, Lee J, Park DW, et al. Clinical outcome and pre- ingoid appearance with long-term use of steroids or ste- dictive factors of recurrence among patients with Kikuchi's roid-dependent, we may suggest treatment with HC as a disease. Int J Infect Dis 2009;13:322-6. 11. Hyun M, So IT, Kim HA, Jung H, Ryu SY. Recurrent Kikuchi's choice. To the best of our knowledge, this patient is the disease treated by hydroxychloroquine. Infect Chemother first case of administering HC in an adolescent patient with 2016;48:127-31. recurrent steroid-dependent KFD in Korea. Thus, we report 12. Uslu E, Gurbuz S, Erden A, et al. Disseminated intravascular successful treatment with HC with recurrent KFD depend- coagulopathy caused by Kikuchi-Fujimoto disease resulting in death: first case report in Turkey. Int Med Case Rep J 2014;7: ent on steroids without any symptoms of autoimmune 19-22. disease. 13. Yoshioka K, Miyashita T, Nakamura T, Inoue T, Yamagami K. Treatment of histiocytic necrotizing lymphadenitis (Kiku- chi's disease) with prolonged fever by a single course of References methylprednisolone pulse therapy without maintenance ther- apy: experience with 13 cases. Intern Med 2010;49:2267-70. 1. Hutchinson CB, Wang E. Kikuchi-Fujimoto disease. Arch 14. Gilman AL, Schultz KR, Goldman FD, et al. Randomized trial Pathol Lab Med 2010;134:289-93. of hydroxychloroquine for newly diagnosed chronic graft-ver- 2. Tsang WY, Chan JK. Fine-needle aspiration cytologic diag- sus-host disease in children: a Children's Oncology Group nosis of Kikuchi's lymphadenitis. A report of 27 cases. Am study. Biol Blood Marrow Transplant 2012;18:84-91. J Clin Pathol 1994;102:454-8. 15. Melles RB, Marmor MF. The risk of toxic retinopathy in pa- 3. Bosch X, Guilabert A. Kikuchi-Fujimoto disease. Orphanet J tients on long-term hydroxychloroquine therapy. JAMA Rare Dis 2006;1:18. Ophthalmol 2014;132:1453-60.

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