Archives of Academic Emergency Medicine. 2019; 7(1): e3 CA S E RE P O RT Kikuchi-Fujimoto Disease in an Iranian Woman; a Rare but Important Cause of Lymphadenopathy Mana Baziboroun1, Masomeh Bayani1∗, Ghodsieh Kamrani2, Shahab Saeedi1, Majid Sharbatdaran2 1. Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran. 2. Department of Pathology, School of Medicine, Babol University of Medical Sciences, Babol, Iran. Received: September 2018; Accepted: October 2018; Published online: 1 January 2019 Abstract: Kikuchi-Fujimoto Disease (KFD), is a rare and self-limited condition of histiocytic necrotizing lymphadenitis, which typically presents as fever and lymphadenopathy. We describe a case of KFD in an Iranian woman. Due to low incidence and high importance, awareness of this disease is necessary for clinicians for early diagnosis and appropriate treatment. A 26-year-old woman was admitted to our hospital with a 3-week history of fever and lymphadenopathy. On physical examination, she had three separate enlarged lymph nodes on the right side of her neck. In laboratory tests that were carried out, she had mild anemia and an increase in C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR) and lactate dehydrogenase (LDH) level, while other tests were normal. Ultasound (U/S) guided core needle lymph node biopsy was performed and based on the histological finding, diagnosis of Kikuchi-Fujimoto disease was made. The patient was managed supportively and with prednisolone. She symptomatically improved and was discharged with no follow up. Although the incidence of KFD is rare, it must be considered as a differential diagnosis of lymphadenopathy especially in tuberculosis-endemic areas like our country-Iran. Moreover, it is necessary that physicians are aware of this disease in order to minimize unnecessary evaluation and toxic treatment. Keywords: Histiocytic necrotizing lymphadenitis; Fever; lymphadenopathy Cite this article as: Baziboroun M, Bayani M, Kamrani Gh, Saeedi Sh, Sharbatdaran M. Kikuchi-Fujimoto Disease in an Iranian Woman; a Rare but Important Cause of Lymphadenopathy. Arch Acad emerg Med. 2019; 7(1): e3. 1. Introduction Kikuchi syndrome, also known as Kikuchi-Fujimoto disease (KFD) is histologically a histiocytic necrotizing lymphadeni- tis. The most common presentation of KFD is cervical lym- phadenopathy with or without constitutional symptoms in previously healthy individuals. This disease often affects women under the age of 30, and is more common in Asia. It is self-limited and resolves spontaneously (1, 2). KFD is an extremely rare disorder. As a result, physicians’ awareness of the disease is minimal (3). The exact cause of the Kikuchi dis- ease is still unknown, but viral or autoimmune causes may have a role. However, the role of viruses is controversial (4). KFD is of clinical significance, as it is confused with other ill- nesses like tuberculosis, lymphoma or systemic lupus erythe- matosus (SLE). No definite laboratory test for KFD has been ∗Corresponding Author: Masomeh Bayani; Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Med- ical Sciences, Babol, Iran. Email: Dr.bayani1@yahoo.com. Tel: +989113112559 found so far, as a result, diagnosis is to be confirmed through biopsy studies (5). Characteristic feature of Kikuchi disease in the excisional biopsy of involved lymph nodes is coagula- tive necrosis with plenty of karyorrhetic debris in paracorti- cal areas (4). In line with the above explanation, an immedi- ate diagnosis and treatment of the disease is important since it prevents unnecessary further tests and patient’s discomfort (6). In the following section, there is a case report of KFD in a young woman here in Babol, north of Iran. 2. Case presentation A 26-year-old woman was admitted to our hospital with a three-week history of fever and painful lymphadenopathy. She initially had observed a painful swelling on the right side of her neck. Later, symptoms such as fever, nausea and fa- tigue were added. Despite the application of antibiotics such as amoxicillin/clavulanate and metronidazole, the swelling in the patient’s neck had enlarged gradually. The patient didn’t have any comorbidity. She was a married housewife, living with her family in a village around Babol-Mazandaran, This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Baziboroun et al. 2 Figure 1: Brain computed tomography scan and magnetic reso- nance imaging of patient. Iran. In addition, she had no recent trip and no signifi- cant family history. On the day of admission, she had stable hemodynamics, but further observation showed three sepa- rate enlarged lymph nodes on the right side of her neck, with- out any changes on the skin covering them. The woman was initially treated with clindamycin and naproxen. Anyhow, during two weeks of hospital stay, she had a fever ranging from 38-40◦C. Laboratory studies demonstrated mild ane- mia (hemoglobin 10.9 gr/dL, normal range 14-18 gr/dL), with normal white blood cell count (6.4/ml, normal range 4.5- 11/mL). Inflammatory markers were increased: C-reactive protein (CRP) level peaked at 77mg/l (normal range < 5 mg/l) and erythrocyte sedimentation rate (ESR) reached 42 mm/hour (normal range 0-20 mm/hour). The patient’s serum lactate dehydrogenase (LDH) level had also increased to 519 U/L (normal range < 480 U/L). Cultures of blood and urine showed no growth and tuberculin skin test was nega- tive. Serological tests detected evidence of previous Epstein- Barr virus (EBV ) infection, but serologic tests for HIV, Hepati- tis B and C, toxoplasmosis, venereal disease research labora- tory (VDRL), ANA and RF were negative. Chest radiography and computed tomography (CT) scan of the chest, abdomen and pelvis were unremarkable. Ultra- sound (U/S) and CT scan of the neck, revealed multiple lym- phadenopathy on both sides of the neck, expanding to the base of the neck and intra parotid. On the right side, lymph nodes in the posterior triangle of the neck, had pathologic morphology, with rim enhancement and hypodense center (central necrosis), up to 18 × 14 mm and on the left side, lymph nodes had a reactive view up to 12 × 5 mm (fig. 1). Figure 2: Brain magnetic resonance angiogram of patient. U/S guided core needle biopsy was performed, which re- vealed an effaced architecture with extensive coagulation necrosis and nuclear karyorrhexis, especially in the paracor- tical zone (fig. 2 A). No plasma cell or neutrophil was present. In an immuno- histochemistry assessment, we found CD68-positive histio- cytes in necrotic areas admixed with numerous CD3-positive T-cells (fig. 2 B&C). B-cells (CD20+) were also seen in remain- ing lymphoid follicles (fig. 2 D). These findings were com- patible with Kikuchi’s lymphadenitis. The patient was man- aged supportively and with prednisolone. After 3 weeks, she symptomatically improved and was discharged with no fol- low up. 3. Discussion Kikuchi-Fujimoto disease is a rare and benign disease that usually improves spontaneously. In a study performed on 244 cases of KFD, 70% of them were younger than 30 years old and 77% were women. Most of the patients come from East Asia (50%) (5, 7). While the etiology of KFD remains unknown, infectious, ge- netic and autoimmune causes have been proposed. Vari- ous infections such as EBV, Herpes viruses, Hepatitis B, Par- vovirus B19, Parainfluenza virus, HTLV1, Human immunod- eficiency virus (HIV ), Rubella, Paramyxovirus, Toxoplasmo- sis, Brucellosis, Bartonella henselae, and Yersiniaenterocolit- ica have been deemed related to the disease. Among them, EBV has been studied more, but its causal relationship has not been proved. Other reports have suggested autoimmune origin, especially SLE. Other autoimmune diseases associ- ated with KFD are as follows: Still’s disease, Sjogren’s syn- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2019; 7(1): e3 drome, Polymyositis and Rheumatoid arthritis. Studies have also found that interferon gamma, interleukin-6 and apop- totic cells probably play a role in KFD. Others have suggested certain food sources, like raw fish, as a cause (1, 8, 9). The onset of Kikuchi disease can be acute or subacute and lasts about 2-3 weeks. Fever in 30-50% of cases is a pri- mary symptom, but the main manifestation of the disease in approximately 80% of cases, is unilateral cervical lym- phadenopathy, such as in our case (10). Although poste- rior cervical and supraclavicular nodes are involved most commonly, the involvement of other lymph nodes is noted uncommonly, such as axillary, inguinal and mediastinal nodes. Generalized lymphadenopathy is even more uncom- mon. Extra nodal extension of KFD has also been rarely re- ported, affecting skin, myocardium, bone marrow, C.N.S and eye movement. Systemic manifestations can also include malaise, headache, night sweats, weight loss and arthralgia (9, 11). No specific laboratory test is available for Kikuchi syndrome. Anemia, leukopenia, raised ESR and CRP, and ele- vated lactate dehydrogenase and immunoglobulin levels can be found in this disease. Elevated levels of transaminases and ferritin are rarely found (11, 12). Our patient had mild anemia, elevated LDH and raised ESR and CRP, with normal transaminases. Diagnosing the cause of the fever and lymphadenopathy, re- quires extensive work-up and considering differential diag- noses like lymphoma, tuberculosis, sarcoidosis, toxoplasmo- sis, cat-scratch disease, mononucleosis, AIDS and SLE; espe- cially in countries where tuberculosis is endemic like Iran, KFD can be confused with tuberculosis clinically (1, 3, 13). Our patient had negative bacteriological cultures and nega- tive viral serological tests. The result of tuberculin skin test was also negative. Clinical and laboratory characteristics in our patient were similar to lymphoma, but unlike lymphoma, enlarged lymph nodes were tender and pathologic results also ruled out lymphoma. The definite diagnosis of Kikuchi syndrome is made by excisional biopsy of affected lymph nodes and histological evaluation. Fine needle aspiration cy- tology (FNAC) is a cheaper, faster and less invasive method, but the accuracy is only 56%. Nevertheless, with clear clinical symptoms and the typical finding of KFD in FNAC, the diag- nosis of Kikuchi disease can be done without lymphadenec- tomy (12), like what happened in our case. But if clinical finding is unusual, histopathological examination of lymph node by ultrasound-guided biopsy can be an optimal diag- nostic method (3). Histological examination reveals paracortical foci of coagula- tion, necrosis and karyorrhetic debris. Histiocyte-associated antigens (lysosome, myeloperoxidase and CD68) are also ex- pressed by histiocytes in KFD. However, for pathologists, dif- ferentiation of Kikuchi disease from other causes of lym- phadenopathy such as SLE and lymphoma is challenging. The absence of plasmacells or neutrophils are other features in KFD, which rule out the diagnosis of SLE. Furthermore, absence of Reed-Sternberg or Hodgkin-like cells, is useful in ruling out leukemic process (10, 14). Although Kikuchi disease is self-limited, has good progno- sis, and usually resolves within 1-6 months, it can be re- current (3-4% of cases) or become complicated with neuro- logical manifestations, hemophagocytic syndromes or heart failure. Very rare cases of fatal outcome have also been reported (10). There is no specific treatment for KFD. The best approach is supportive and symptomatic therapy with analgesics and nonsteroidal anti-inflammatory drugs (NSAIDS). However glucocorticoids can be considered to re- duce fever and painful lymphadenopathy, especially in gen- eralized and complicated cases; furthermore, there are case reports of successful treatments with hydroxychloroquine, cyclosporine, azathioprine and intravenous immunoglobu- lin (1, 11). 4. Conclusions This case report highlights the importance of Kikuchi dis- ease as differential diagnosis of lymphadenopathy, especially in endemic areas for tuberculosis like our country; because this disease can be easily mistaken for TB, lymphoma and so on. So, although the incidence of KFD is rare, physi- cian’s awareness of this disease is the key to timely diagnosis and minimizing unnecessary evaluations and inappropriate treatment. 5. Appendix 5.1. Acknowledgements The authors express their appreciation to department of in- fectious diseases, Babol University of Medical Sciences. 5.2. Authors’ contribution All authors met the four criteria for authorship contribution based on the recommendations of the international com- mittee of medical journal editors. Authors ORCIDs Masomeh Bayani: 0000-0003-3044-1168 Ghodsieh Kamrani: 0000-0001-6553-4693 Majid Sharbatdaran: 0000-0002-9894-5592 5.3. Conflict of interest The authors declare that theres is no conflict of interest. 5.4. Funding None. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Baziboroun et al. 4 References 1. Shahid S, Alam SH, Hadley I. An Unusual Presentation of Kikuchi-Fujimoto Disease with Recurrent Subdural Effu- sion. Cureus. 2018;10(3):e2302. 2. Lamzaf L, Harmouche H, Maamar M, Adnaoui M, Aouni M, Tazi Mezalek Z. Kikuchi-Fujimoto disease: report of 4 cases and review of the literature. 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