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The incidence and clinical characteristics by gender differences in patients with Kikuchi–Fujimoto disease

The incidence and clinical characteristics by gender differences in patients with... Kikuchi–Fujimoto disease (KFD) is a rare, self-limiting disorder that typically affects the cervical lymph nodes (LNs). Although initially described in young women, KFD also occurs in men. There are no reports on the clinical manifestations and characteristics of male KFD patients. Therefore, this study was conducted to assess the incidence of KFD among males, as well as the most frequent clinical characteristics of these patients. A retrospective, cross-sectional study was performed at a tertiary hospital of patients pathologically confirmed as having KFD from LN biopsy specimens. Clinical and laboratory data, and treatment outcomes of the enrolled patients, were analyzed by gender. A total of 254 patients diagnosed with KFD were enrolled. There were 189 females and 65 males (2.9:1). The mean age was 32.6±11.3 years. Compared to the female patients, the males had more frequent manifestations of fever (48% vs 67%, P=0.008), headache (9% vs 20%, P=0.013), bilateral lymphadenopathy (31% vs 46%, P=0.029), thrombocytopenia (14% vs 29%, P=0.014), elevated C-reactive protein (CRP) (35% vs 78.4%, P<0.001), elevated liver enzymes (15% vs 41%, P<0.001), and elevated lactate dehydrogenase (LDH) (61% vs 80%, P=0.021). Male patients had fewer autoimmune features (9% vs 2%, P= 0.043) and fewer positive antinuclear antibodies (32% vs 10%, P=0.006). In this study, 25.6% of the enrolled patients were male, with a 2.9:1 female-to-male sex ratio. Male patients showed a distinctive profile characterized by a higher frequency of fever, headache, bilateral lymphadenopathy, and thrombocytopenia, as well as elevated liver enzymes, CRP, and LDH. Abbreviations: ANA = antinuclear antibody, AOSD = adult-onset Still disease, CKD = chronic kidney disease, CRP = C-reactive protein, ESR = erythrocyte sedimentation rate, KFD = Kikuchi–Fujimoto disease, LDH = lactate dehydrogenase, LFT = liver function test, LN = lymph node, MCD = mixed connective tissue disease, NSAID = nonsteroidal anti-inflammatory drugs, SLE = systemic lupus erythematosus. Keywords: characteristics, Kikuchi–Fujimoto disease, males unknown, but an immune response of T cells and histiocytes to an 1. Introduction [6] infectious agent is considered to be the most probable cause. Kikuchi–Fujimoto disease (KFD), also known as histiocytic [7] KFD has been most frequently been reported in Asia, but has necrotizing lymphadenitis, was first reported in Japan in [8] been identified in many ethnic groups in various countries. [1–4] 1972. It is a rare cause of lymphadenopathy, characterized KFD mainly occurs at a young age and has been reported to occur by cervical lymphadenopathy, fever, and leukopenia, which is [9–11] more frequently in women. The male-to-female sex ratio [5] usually clinically benign. The pathogenesis of KFD remains [9–13] varies from 1:16 to 1:4. The sex distribution is almost equal in adult Asian populations, but among children aged 18 years or [14] younger, male predominance has been reported (8:3). Editor: Giovanni Tarantino. Prior studies on the clinical manifestations and outcomes of IYJ and HWA have contributed equally to the article as first coauthors. KFD have focused on females, and few studies exist on KFD The authors have no conflicts of interest to disclose. among young men. Furthermore, to the best of our knowledge, a b Department of Internal Medicine, AIDS Research Institute, Yonsei University there have been no larger scale reports on differences in clinical College of Medicine, Seoul, Republic of Korea. manifestations by gender. Therefore, the aim of this study was to Correspondence: Nam Su Ku, Department of Internal Medicine, Yonsei identify the male incidence of KFD and investigate the clinical University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, 120-752 Seoul, manifestations and laboratory features that are more frequently Republic of Korea (e-mail: smileboy9@yuhs.ac) observed in male KFD patients. Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is 2. Methods permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission 2.1. Study design from the journal. A retrospective, observational cohort study was performed at a Medicine (2017) 96:11(e6332) 2000-bed tertiary hospital in South Korea, from December 1995 Received: 29 November 2016 / Received in final form: 12 February 2017 / Accepted: 16 February 2017 to December 2014. Patients aged 18 years or older, with regional or generalized lymphadenopathy, and compatible histologic http://dx.doi.org/10.1097/MD.0000000000006332 1 Jung et al. Medicine (2017) 96:11 Medicine findings (histiocytes and lymphoid cell aggregates or subacute test. A P value <0.05 was considered statistically significant. necrotizing lymphadenopathy) in histology analyses from lymph Analyses were performed using SPSS software (ver. 23.0; SPSS [15] node (LN) biopsy specimens were defined as KFD. Patients Inc., Chicago, IL). diagnosed with a concurrent malignant lymphoma or tuberculo- sis were excluded from the study. Patients lacking imaging data 3. Results (computed tomography or ultrasonography of the neck) or A total of 284 patients were diagnosed with KFD during the study sufficient medical records regarding their clinical symptoms were period. After excluding 30 patients (20 patients had no imaging also excluded. This study was approved by the ethics committee data, 7 had incomplete medical records, and 3 were diagnosed of the Yonsei University College of Medicine Severance Hospital. with concurrent tuberculosis), 254 patients were finally enrolled Informed consent was waived from all patients. in this study (Fig. 1). The following variables were assessed: demographic and Of these patients, 25.6% (n=65) were male, and the female-to- baseline clinical characteristics (age, gender, presence of male sex ratio was 2.91:1. The mean age at diagnosis was 30.5± hypertension, diabetes, malignant disease, chronic kidney disease 11.0 years in males and 30.0±9.3 years in females. There were no [CKD], and autoimmune diseases), clinical signs and symptoms significant differences in age or underlying disease, except for at diagnosis (pain, fever, night sweats, sore throat, weight loss, autoimmune diseases, between males and females. Seventeen rash, myalgia, arthralgia, nausea, and headache), lymphadenop- female subjects had been diagnosed with an autoimmune disease, athy features (duration of onset, lesions [cervical, extracervical, which showed a female predominance, as only 1 male patient had single, or multiple], size of the largest LN, laterality, and sites of a history of autoimmune disease (n=17 [9%] vs n=1 [2%], P= cervical involvement) and laboratory results (complete blood cell 0.043). There were no patients in this study who were diagnosed counts, erythrocyte sedimentation rate [ESR], C-reactive protein with rheumatoid arthritis, systemic sclerosis, polymyositis/ [CRP], liver function tests [LFTs], lactate dehydrogenase [LDH], dermatomyositis, or vasculitis. There was 1 patient who was and antinuclear antibodies [ANAs]), and outcomes (treatment diagnosed with mixed connective tissue disease (MCD) (Table 1). options, cure or relapse, and all-cause mortality). In this study, male patients experienced fever (n=90 [48%] vs n=43 [67%], P=0.008) and headache (n=16 [9%] vs n=13 2.2. Definitions [20%], P=0.013) more frequently than females. The duration of Patients with malignancy included those with a history of solid fever was shorter in male patients, with a mean duration of 8 organ cancer or hematologic malignancy at the time of KFD days, compared to 13 days in females (P=0.014). Fever (67%), diagnosis. Diabetes was defined based on the American Diabetes tenderness on the affected LN (32%), and headache (20%) were [16] Association diagnostic criteria. Hypertension was defined in the most frequent symptoms experienced by male patients. Male patients with a systolic blood pressure of 140mm Hg or more, or patients also had more frequent bilateral LN involvement a diastolic blood pressure of 90mm Hg or more, or taking compared to females (n=59 [31%] vs n=30 [46%], P= [17] antihypertensive medication. CKD was defined as either 0.029). Cervical lymphadenopathy was seen in 95.7% of the kidney damage or a decreased glomerular filtration rate of less total subjects, with no difference observed between genders. The 2 [18] than 60mL/min/1.73m for at least 3 months. Autoimmune duration of onset, or size, or site of cervical involvement also disease was defined in patients diagnosed with systemic lupus showed no difference between the genders (Table 1). erythematosus (SLE), adult-onset Still disease (AOSD), Sjögren Thrombocytopenia was more frequently observed in male syndrome, or Behçet disease. versus female patients (22 [14%] vs 17 [29%], P=0.014). Male Fever was defined as a temperature over 38.0 °C as an initial patients also had more frequent abnormal LFTs (21 [15%] vs 24 symptom. A headache was defined as symptoms lasting for more [41%], P<0.001), elevated serum LDH (62 [61%] vs 39 [80%], than a week. Extracervical LN involvement was defined as involvement of the axillary, mesenteric, or inguinal LNs. Multiple LN involvement was defined as having multiple levels of cervical lymphadenopathy. Relapse was defined as pathologically proven KFD on rebiopsy due to recurring symptoms of fever or lymphadenopathy during a 3-month follow-up. Leukopenia was defined as a white blood cell count lower than 4000 cells/mL. Neutropenia was defined as an absolute neutrophil count of lower than 1500 cells/mL. Anemia was [11] defined as having a hemoglobin level lower than 12g/dL. Thrombocytopenia was defined as a platelet count below [19] 150,000 cells/mL. Elevated ESR was defined as a level [11] exceeding 60mm/h. Elevated CRP was defined as a level [11] exceeding 8mg/L. An abnormal LFT was defined as an alanine [11] aminotransferase level exceeding 40IU/L. Elevated LDH was [11] defined as a level exceeding 500IU/L. 2.3. Data analysis Normally distributed continuous variables are expressed as means±standard deviation, and categorical variables are presented as numbers and percentages. The statistical significance Figure 1. Patient inclusion algorithm. of the comparisons was assessed using a paired t test and the x 2 Jung et al. Medicine (2017) 96:11 www.md-journal.com Table 1 Table 2 The baseline characteristics and clinical features of the patients. The laboratory findings of the patients. Female (n= 189) Male (n= 65) P Female (n= 189) Male (n= 65) P Age, y 30.0± 9.3 30.5± 11.0 0.870 Laboratory findings (n, %) Underlying diseases (n, %) Leukopenia 86 (55.8) 33 (55.9) 0.991 Malignancy 11 (5.8) 5 (7.7) 0.592 Neutropenia 86 (55.8) 33 (55.9) 0.991 Diabetes 1 (0.5) 0 (0) 1.000 Anemia 44 (28.6) 13 (22.0) 0.335 Hypertension 2 (1.1) 0 (0) 1.000 Thrombopenia 22 (14.3) 17 (28.8) 0.014 CKD 0 (0) 1 (1.5) 0.256 Elevated ESR 107 (56.6) 41 (63.1) 0.362 Autoimmune disease 17 (9.0) 1 (1.5) 0.043 ESR, mm/h, mean± SD 43.0± 26.0 38.8± 22.7 0.312 SLE 9 (4.8) 1 (1.5) 0.249 Elevated CRP 41 (35.0) 40 (78.4) <0.001 AOSD 3 (1.6) 0 (0) 0.572 CRP, g/dL, mean± SD 17.2± 35.2 41.6± 1.6 0.003 Sjögren 3 (1.6) 0 (0) 0.572 Abnormal LFTs 21 (14.7) 24 (41.4) <0.001 Behçet 2 (1.1) 0 (0) 1.000 Elevated LDH 62 (60.8) 39 (79.6) 0.021 MCD 1 (0.5) 0 (0) 1.000 ANA positivity 32 (31.7) 4 (9.8) 0.006 Clinical manifestation (n, %) ANA = antinuclear antibody, CRP = C-reactive protein, ESR = erythrocyte sedimentation rate, LDH = Pain 75 (40.1) 20 (31.7) 0.237 lactate dehydrogenase, LFT = liver function test. Fever (≥38.0 °C) 90 (48.1) 43 (67.2) 0.008 Fever duration, d 13± 20.9 8± 13.4 0.014 Night sweat 6 (3.2) 6 (9.2) 0.083 4. Discussion Sore throat 19 (10.2) 9 (13.8) 0.415 Weight loss (≥10%) 18 (9.6) 6 (9.2) 0.926 In this study, the ratio of KFD-affected females to males was Rash 12 (6.4) 3 (4.6) 0.597 [14] 2.9:1. A study by Seo et al, of Korean individuals younger than Myalgia 25 (13.4) 10 (15.4) 0.686 18 years of age, showed no difference in KFD incidence by Arthralgia 12 (6.4) 2 (3.1) 0.311 [20] gender. However, Kang et al reported a female-to-male sex Nausea 10 (5.3) 4 (6.2) 0.807 ratio of KFD of 1.32:1 among Korean children. This difference Headache 16 (8.6) 13 (20.0) 0.013 may be explained by the age differences of the patients between Lymphadenopathy (n, %) these studies, where the median ages were 13.2 and 12.45 years, Involved LN One level cervical LN 179 (94.7) 64 (98.5) 0.200 respectively. In 3 studies on adults, the ratios of affected females [9,10,12] Multiple levels of cervical LNs 176 (93.1) 62 (95.4) 0.517 to males were 4:1, 1.6:1, and 1.26:1, respectively. Extracervical LNs 29 (15.3) 17 (26.2) 0.051 Among our male patients, fever (67%), tenderness on the Size, cm affected LN (32%), and headache (20%) were the most frequent <1 18 (9.5) 3 (4.6) 0.215 symptoms. Although tenderness of the affected site showed no 1–2 116 (61.4) 37 (56.9) 0.527 difference between genders, headache (20%) was more frequent >2 50 (26.5) 24 (36.9) 0.109 in male patients. Fever was also more frequent in males, with Laterality 67% of male patients presenting with fever as an initial symptom. Left 64 (33.9) 18 (22.7) 0.359 However, the total duration of fever was longer in female Right 65 (34.4) 17 (26.2) 0.220 patients, with a mean duration of 13±20.9 days. In a Both 59 (31.2) 30 (46.2) 0.029 [13] retrospective review by Kucukardali et al of 244 KFD patients Onset, mo Less than 1 131 (69.3) 50 (76.9) 0.242 (in which 77% of the patients were female), fever (35%), fatigue 1–2 47 (24.9) 11 (16.9) 0.188 (7%), and joint pain (7%) were the most frequent symptoms. The More than 2 10 (5.3) 4 (6.2) 0.793 most common symptoms of the female patients in this study were Cervical site fever (48%), tenderness of the affected LN (40%), and myalgia Anterior triangle 17 (9.0) 4 (6.2) 0.473 (13%). Arthralgia was present in 6% of the female patients, Posterior triangle 155 (82.0) 54 (83.1) 0.846 similar to the results of the Kucukardali study. Both triangles 17 (9.0) 7 (10.8) 0.673 A study conducted in the United States showed that 83% of Data are expressed as the mean± standard deviation or n (%). AOSD = adult onset Still disease, CKD patients had localized lymphadenopathy, particularly of the = chronic kidney disease, LN = lymph node, MCD = mixed connective tissue disease, SLE = [12] posterior cervical area. In another study of 79 Chinese systemic lupus erythematosus. patients, 97% presented with cervical lymphadenopathy, and Extracervical LN: para-aortic, mesenteric lymph nodes. [21] there was bilateral involvement in 18 (22%) patients. In this P=0.021), and elevated CRP (41 [35%] vs 40 [78.4%], P< 0.001). However, ANA positivity was significantly more frequent Table 3 in female patients (32 [32%] vs 4 [10%], P=0.006) (Table 2). The treatment outcomes of the patients. Regarding the final outcomes, 35.8% of patients showed Female (n= 189) Male (n= 65) P spontaneous clinical improvement, that is, improvement without Treatment (n, %) treatment. Monotherapy, of steroids or nonsteroidal anti- No treatment 67 (35.4) 24 (36.9) 0.831 inflammatory drugs (NSAIDs), was administered to 18% and Steroid 36 (19.0) 10 (15.4) 0.508 33.8% of the patients, respectively; 12% of the patients received NSAIDs 67 (35.4) 19 (29.2) 0.361 both types of treatment. Pathologically proven relapse and Both 19 (10.1) 12 (18.5) 0.074 disease-related mortality occurred more frequently in female Relapse (n, %) 2 (1.1) 0 (0) 0.405 patients, but there was no statistically significant difference Death (n, %) 4 (2.1) 0 (0) 0.237 between males and females (4 [2%] vs 0 [0%], P=0.237) NSAID = nonsteroidal anti-inflammatory drug. (Table 3). 3 Jung et al. Medicine (2017) 96:11 Medicine study, 95.7% of patients presented with cervical lymphadenopa- presented with autoimmune disorders and ANA positivity more thy, most frequently in the posterior cervical triangle. In total, frequently. 46% of male patients had bilateral lymphadenopathy, while this was seen in only 31% of the female patients. The results in this References study are similar to those of previous studies, in which KFD commonly presented as posterior cervical lymphadenopathy, and [1] Fujimoto Y, Kozima Y, Hamaguchi K. Cervical necrotizing lymphade- they show that male patients present with bilateral lymphade- nitis: a new clinicopathological agent. Naika 1972;20:920–7. [2] Kikuchi M. Lymphadenitis showing focal reticulum cell hyperplasia with nopathy more frequently than females. nuclear debris and phagocytosis. Nippon Ketsueki Gakkai Zasshi 1972; In this study, elevated LDH (80%), leukopenia (56%), elevated 35:378–80. CRP (78.4%), and elevated liver enzymes (41%) were the most [3] Yen A, Fearneyhough P, Raimer SS, et al. EBV-associated Kikuchi’s frequent laboratory findings in male patients. Furthermore, histiocytic necrotizing lymphadenitis with cutaneous manifestations. J Am Acad Dermatol 1997;36:342–6. thrombocytopenia, elevated liver enzymes, and LDH are all [4] Hudnall SD, Chen T, Amr S, et al. Detection of human herpesvirus DNA markers of severe inflammation and were seen more frequently in in Kikuchi–Fujimoto disease and reactive lymphoid hyperplasia. Int J [22] male patients. Keogh et al reported a case of a young man Clin Exp Pathol 2008;1:362–8. diagnosed with KFD who developed respiratory failure, [5] Dorfman RF. Histiocytic necrotizing lymphadenitis of Kikuchi and Fujimoto. Arch Pathol Lab Med 1987;111:1026–9. parotidomegaly, and thyroiditis, requiring intensive care unit [6] Anagnostopoulos I, Hummel M, Korbjuhn P, et al. Epstein-Barr virus in management. These findings suggest that KFD in males may be Kikuchi–Fujimoto disease. Lancet 1993;341:893. more commonly associated with severe systemic inflammation [7] Dalton J, Shaw R, Democratis J. Kikuchi–Fujimoto disease. Lancet and presents as a more severe form of illness compared to that 2014;383:1098. seen in females. These findings are consistent with the results of [8] Turner RR, Martin J, Dorfman RF. Necrotizing lymphadenitis. A study [13] of 30 cases. Am J Surg Pathol 1983;7:115–23. previous studies. [9] Lin HC, Su CY, Huang CC, et al. Kikuchi’s disease: a review and analysis An autoimmune mechanism is often proposed in KFD, since of 61 cases. Otolaryngol Head Neck Surg 2003;128:650–3. many studies have described an association between KFD and [10] Asano S, Akaike Y, Jinnouchi H, et al. Necrotizing lymphadenitis: a [23,24] SLE. In this study, SLE was present in 9 (5%) female review of clinicopathological, immunohistochemical and ultrastructural patients and 1 (2%) male patient. This shows that autoimmune studies. Hematol Oncol 1990;8:251–60. [11] Rakesh P, Alex RG, Varghese GM, et al. Kikuchi–Fujimoto disease: diseases are more frequent in females, which agrees with the [10] clinical and laboratory characteristics and outcome. J Glob Infect Dis results of previous studies. Since KFD and SLE share similar 2014;6:147–50. sex and age profiles, that is, occur more often in young [12] Dorfman RF, Berry GJ. Kikuchi’s histiocytic necrotizing lymphadenitis: [25] females, several studies recommend ANA testing in patients an analysis of 108 cases with emphasis on differential diagnosis. Semin [10,12] Diagn Pathol 1988;5:329–45. initially diagnosed with KFD to exclude concomitant SLE. [13] Kucukardali Y, Solmazgul E, Kunter E, et al. Kikuchi–Fujimoto disease: In this study, the ANA-positive rate was also higher among analysis of 244 cases. Clin Rheumatol 2007;26:50–4. females. [14] Seo JH, Shim HS, Park JJ, et al. A clinical study of histiocytic necrotizing In the majority of patients, KFD is a benign, self-limiting lymphadenitis (Kikuchi’s disease) in children. Int J Pediatr Otorhinolar- [15] disease. Our study results did not differ from those of previous yngol 2008;72:1637–42. [15] Song JY, Lee J, Park DW, et al. Clinical outcome and predictive factors of studies, with more than 35% of the patients showing a recurrence among patients with Kikuchi’s disease. Int J Infect Dis spontaneous resolution without any specific treatment. Death 2009;13:322–6. occurred in 4 female patients, and there was no KFD-related [16] American Diabetes Association. Diagnosis and classification of diabetes mortality in the male patients. No male, and only 2 female, mellitus. Diabetes Care 2010;33(Suppl 1):S62–9. [26] [17] Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke patients experienced a single episode of relapse. Smith et al statistics—2016 update: a report from the American Heart Association. reported a female patient with 4 episodes of recurrent KFD over a Circulation 2016;133:e38–60. period of 18 years. However, as our study only enrolled patients [18] Kirsztajn GM, Filho NS, Draibe SA, et al. Fast reading of the KDIGO with histologically proven KFD, the recurrence rate may have 2012: guidelines for evaluation and management of chronic kidney disease in clinical practice. J Bras Nefrol 2014;36:63–73. been underestimated. [19] Williamson DR, Albert M, Heels-Ansdell D, et al. Thrombocytopenia in There were several limitations to this study. First, it was critically ill patients receiving thromboprophylaxis: frequency, risk conducted retrospectively, and cases without sufficient clinical factors, and outcomes. Chest 2013;144:1207–15. data on the symptoms were excluded. This may have resulted in a [20] Kang HM, Kim JY, Choi EH, et al. Clinical characteristics of severe reduced number of patients with KFD being enrolled. Second, histiocytic necrotizing lymphadenitis (Kikuchi–Fujimoto disease) in children. J Pediatr 2016;171:208–12.e1. only cases that were histopathologically confirmed at initial [21] Kuo TT. Kikuchi’s disease (histiocytic necrotizing lymphadenitis). A diagnosis and recurrence were included. Those patients who were clinicopathologic study of 79 cases with an analysis of histologic very likely to have KFD based solely on their clinical data were subtypes, immunohistology, and DNA ploidy. Am J Surg Pathol not included. Third, a total of 15 patients (12 patients on steroids; 1995;19:798–809. 6 for SLE, 2 for Sjogren disease, 1 for Behçet disease, 2 for AOSD, [22] Keogh MA, Williamson RM, Denaro CP. Kikuchi’s disease associated with parotidomegaly, thyroiditis and a rash in a young man. Aust N Z J 1 for MCD, and 3 patients on NSAIDs due to SLE) already Med 2000;30:633–4. receiving NSAIDs or steroids for treating autoimmune diseases [23] Meyer O, Kahn MF, Grossin M, et al. Parvovirus B19 infection can were included in the study, and this may have interfered with the induce histiocytic necrotizing lymphadenitis (Kikuchi’s disease) associ- evaluation. ated with systemic lupus erythematosus. Lupus 1991;1:37–41. [24] Louis N, Hanley M, Davidson NM. Kikuchi–Fujimoto disease: a report In conclusion, 25.6% of enrolled patients were males, with a of two cases and an overview. J Laryngol Otol 1994;108:1001–4. 2.9:1 female-to-male sex ratio. Male patients showed a distinct [25] Patra A, Bhattacharya SK. SLE developing in a follow-up patient of profile characterized by a higher frequency of fever, headache, Kikuchi’s disease: a rare disorder. J Clin Diagn Res 2013;7:752–3. bilateral lymphadenopathy, and thrombocytopenia, as well as [26] Smith KG, Becker GJ, Busmanis I. Recurrent Kikuchi’s disease. Lancet 1992;340:124. elevated liver enzymes, CRP, and LDH. Female patients http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Medicine Pubmed Central

The incidence and clinical characteristics by gender differences in patients with Kikuchi–Fujimoto disease

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Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.
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Abstract

Kikuchi–Fujimoto disease (KFD) is a rare, self-limiting disorder that typically affects the cervical lymph nodes (LNs). Although initially described in young women, KFD also occurs in men. There are no reports on the clinical manifestations and characteristics of male KFD patients. Therefore, this study was conducted to assess the incidence of KFD among males, as well as the most frequent clinical characteristics of these patients. A retrospective, cross-sectional study was performed at a tertiary hospital of patients pathologically confirmed as having KFD from LN biopsy specimens. Clinical and laboratory data, and treatment outcomes of the enrolled patients, were analyzed by gender. A total of 254 patients diagnosed with KFD were enrolled. There were 189 females and 65 males (2.9:1). The mean age was 32.6±11.3 years. Compared to the female patients, the males had more frequent manifestations of fever (48% vs 67%, P=0.008), headache (9% vs 20%, P=0.013), bilateral lymphadenopathy (31% vs 46%, P=0.029), thrombocytopenia (14% vs 29%, P=0.014), elevated C-reactive protein (CRP) (35% vs 78.4%, P<0.001), elevated liver enzymes (15% vs 41%, P<0.001), and elevated lactate dehydrogenase (LDH) (61% vs 80%, P=0.021). Male patients had fewer autoimmune features (9% vs 2%, P= 0.043) and fewer positive antinuclear antibodies (32% vs 10%, P=0.006). In this study, 25.6% of the enrolled patients were male, with a 2.9:1 female-to-male sex ratio. Male patients showed a distinctive profile characterized by a higher frequency of fever, headache, bilateral lymphadenopathy, and thrombocytopenia, as well as elevated liver enzymes, CRP, and LDH. Abbreviations: ANA = antinuclear antibody, AOSD = adult-onset Still disease, CKD = chronic kidney disease, CRP = C-reactive protein, ESR = erythrocyte sedimentation rate, KFD = Kikuchi–Fujimoto disease, LDH = lactate dehydrogenase, LFT = liver function test, LN = lymph node, MCD = mixed connective tissue disease, NSAID = nonsteroidal anti-inflammatory drugs, SLE = systemic lupus erythematosus. Keywords: characteristics, Kikuchi–Fujimoto disease, males unknown, but an immune response of T cells and histiocytes to an 1. Introduction [6] infectious agent is considered to be the most probable cause. Kikuchi–Fujimoto disease (KFD), also known as histiocytic [7] KFD has been most frequently been reported in Asia, but has necrotizing lymphadenitis, was first reported in Japan in [8] been identified in many ethnic groups in various countries. [1–4] 1972. It is a rare cause of lymphadenopathy, characterized KFD mainly occurs at a young age and has been reported to occur by cervical lymphadenopathy, fever, and leukopenia, which is [9–11] more frequently in women. The male-to-female sex ratio [5] usually clinically benign. The pathogenesis of KFD remains [9–13] varies from 1:16 to 1:4. The sex distribution is almost equal in adult Asian populations, but among children aged 18 years or [14] younger, male predominance has been reported (8:3). Editor: Giovanni Tarantino. Prior studies on the clinical manifestations and outcomes of IYJ and HWA have contributed equally to the article as first coauthors. KFD have focused on females, and few studies exist on KFD The authors have no conflicts of interest to disclose. among young men. Furthermore, to the best of our knowledge, a b Department of Internal Medicine, AIDS Research Institute, Yonsei University there have been no larger scale reports on differences in clinical College of Medicine, Seoul, Republic of Korea. manifestations by gender. Therefore, the aim of this study was to Correspondence: Nam Su Ku, Department of Internal Medicine, Yonsei identify the male incidence of KFD and investigate the clinical University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, 120-752 Seoul, manifestations and laboratory features that are more frequently Republic of Korea (e-mail: smileboy9@yuhs.ac) observed in male KFD patients. Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is 2. Methods permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission 2.1. Study design from the journal. A retrospective, observational cohort study was performed at a Medicine (2017) 96:11(e6332) 2000-bed tertiary hospital in South Korea, from December 1995 Received: 29 November 2016 / Received in final form: 12 February 2017 / Accepted: 16 February 2017 to December 2014. Patients aged 18 years or older, with regional or generalized lymphadenopathy, and compatible histologic http://dx.doi.org/10.1097/MD.0000000000006332 1 Jung et al. Medicine (2017) 96:11 Medicine findings (histiocytes and lymphoid cell aggregates or subacute test. A P value <0.05 was considered statistically significant. necrotizing lymphadenopathy) in histology analyses from lymph Analyses were performed using SPSS software (ver. 23.0; SPSS [15] node (LN) biopsy specimens were defined as KFD. Patients Inc., Chicago, IL). diagnosed with a concurrent malignant lymphoma or tuberculo- sis were excluded from the study. Patients lacking imaging data 3. Results (computed tomography or ultrasonography of the neck) or A total of 284 patients were diagnosed with KFD during the study sufficient medical records regarding their clinical symptoms were period. After excluding 30 patients (20 patients had no imaging also excluded. This study was approved by the ethics committee data, 7 had incomplete medical records, and 3 were diagnosed of the Yonsei University College of Medicine Severance Hospital. with concurrent tuberculosis), 254 patients were finally enrolled Informed consent was waived from all patients. in this study (Fig. 1). The following variables were assessed: demographic and Of these patients, 25.6% (n=65) were male, and the female-to- baseline clinical characteristics (age, gender, presence of male sex ratio was 2.91:1. The mean age at diagnosis was 30.5± hypertension, diabetes, malignant disease, chronic kidney disease 11.0 years in males and 30.0±9.3 years in females. There were no [CKD], and autoimmune diseases), clinical signs and symptoms significant differences in age or underlying disease, except for at diagnosis (pain, fever, night sweats, sore throat, weight loss, autoimmune diseases, between males and females. Seventeen rash, myalgia, arthralgia, nausea, and headache), lymphadenop- female subjects had been diagnosed with an autoimmune disease, athy features (duration of onset, lesions [cervical, extracervical, which showed a female predominance, as only 1 male patient had single, or multiple], size of the largest LN, laterality, and sites of a history of autoimmune disease (n=17 [9%] vs n=1 [2%], P= cervical involvement) and laboratory results (complete blood cell 0.043). There were no patients in this study who were diagnosed counts, erythrocyte sedimentation rate [ESR], C-reactive protein with rheumatoid arthritis, systemic sclerosis, polymyositis/ [CRP], liver function tests [LFTs], lactate dehydrogenase [LDH], dermatomyositis, or vasculitis. There was 1 patient who was and antinuclear antibodies [ANAs]), and outcomes (treatment diagnosed with mixed connective tissue disease (MCD) (Table 1). options, cure or relapse, and all-cause mortality). In this study, male patients experienced fever (n=90 [48%] vs n=43 [67%], P=0.008) and headache (n=16 [9%] vs n=13 2.2. Definitions [20%], P=0.013) more frequently than females. The duration of Patients with malignancy included those with a history of solid fever was shorter in male patients, with a mean duration of 8 organ cancer or hematologic malignancy at the time of KFD days, compared to 13 days in females (P=0.014). Fever (67%), diagnosis. Diabetes was defined based on the American Diabetes tenderness on the affected LN (32%), and headache (20%) were [16] Association diagnostic criteria. Hypertension was defined in the most frequent symptoms experienced by male patients. Male patients with a systolic blood pressure of 140mm Hg or more, or patients also had more frequent bilateral LN involvement a diastolic blood pressure of 90mm Hg or more, or taking compared to females (n=59 [31%] vs n=30 [46%], P= [17] antihypertensive medication. CKD was defined as either 0.029). Cervical lymphadenopathy was seen in 95.7% of the kidney damage or a decreased glomerular filtration rate of less total subjects, with no difference observed between genders. The 2 [18] than 60mL/min/1.73m for at least 3 months. Autoimmune duration of onset, or size, or site of cervical involvement also disease was defined in patients diagnosed with systemic lupus showed no difference between the genders (Table 1). erythematosus (SLE), adult-onset Still disease (AOSD), Sjögren Thrombocytopenia was more frequently observed in male syndrome, or Behçet disease. versus female patients (22 [14%] vs 17 [29%], P=0.014). Male Fever was defined as a temperature over 38.0 °C as an initial patients also had more frequent abnormal LFTs (21 [15%] vs 24 symptom. A headache was defined as symptoms lasting for more [41%], P<0.001), elevated serum LDH (62 [61%] vs 39 [80%], than a week. Extracervical LN involvement was defined as involvement of the axillary, mesenteric, or inguinal LNs. Multiple LN involvement was defined as having multiple levels of cervical lymphadenopathy. Relapse was defined as pathologically proven KFD on rebiopsy due to recurring symptoms of fever or lymphadenopathy during a 3-month follow-up. Leukopenia was defined as a white blood cell count lower than 4000 cells/mL. Neutropenia was defined as an absolute neutrophil count of lower than 1500 cells/mL. Anemia was [11] defined as having a hemoglobin level lower than 12g/dL. Thrombocytopenia was defined as a platelet count below [19] 150,000 cells/mL. Elevated ESR was defined as a level [11] exceeding 60mm/h. Elevated CRP was defined as a level [11] exceeding 8mg/L. An abnormal LFT was defined as an alanine [11] aminotransferase level exceeding 40IU/L. Elevated LDH was [11] defined as a level exceeding 500IU/L. 2.3. Data analysis Normally distributed continuous variables are expressed as means±standard deviation, and categorical variables are presented as numbers and percentages. The statistical significance Figure 1. Patient inclusion algorithm. of the comparisons was assessed using a paired t test and the x 2 Jung et al. Medicine (2017) 96:11 www.md-journal.com Table 1 Table 2 The baseline characteristics and clinical features of the patients. The laboratory findings of the patients. Female (n= 189) Male (n= 65) P Female (n= 189) Male (n= 65) P Age, y 30.0± 9.3 30.5± 11.0 0.870 Laboratory findings (n, %) Underlying diseases (n, %) Leukopenia 86 (55.8) 33 (55.9) 0.991 Malignancy 11 (5.8) 5 (7.7) 0.592 Neutropenia 86 (55.8) 33 (55.9) 0.991 Diabetes 1 (0.5) 0 (0) 1.000 Anemia 44 (28.6) 13 (22.0) 0.335 Hypertension 2 (1.1) 0 (0) 1.000 Thrombopenia 22 (14.3) 17 (28.8) 0.014 CKD 0 (0) 1 (1.5) 0.256 Elevated ESR 107 (56.6) 41 (63.1) 0.362 Autoimmune disease 17 (9.0) 1 (1.5) 0.043 ESR, mm/h, mean± SD 43.0± 26.0 38.8± 22.7 0.312 SLE 9 (4.8) 1 (1.5) 0.249 Elevated CRP 41 (35.0) 40 (78.4) <0.001 AOSD 3 (1.6) 0 (0) 0.572 CRP, g/dL, mean± SD 17.2± 35.2 41.6± 1.6 0.003 Sjögren 3 (1.6) 0 (0) 0.572 Abnormal LFTs 21 (14.7) 24 (41.4) <0.001 Behçet 2 (1.1) 0 (0) 1.000 Elevated LDH 62 (60.8) 39 (79.6) 0.021 MCD 1 (0.5) 0 (0) 1.000 ANA positivity 32 (31.7) 4 (9.8) 0.006 Clinical manifestation (n, %) ANA = antinuclear antibody, CRP = C-reactive protein, ESR = erythrocyte sedimentation rate, LDH = Pain 75 (40.1) 20 (31.7) 0.237 lactate dehydrogenase, LFT = liver function test. Fever (≥38.0 °C) 90 (48.1) 43 (67.2) 0.008 Fever duration, d 13± 20.9 8± 13.4 0.014 Night sweat 6 (3.2) 6 (9.2) 0.083 4. Discussion Sore throat 19 (10.2) 9 (13.8) 0.415 Weight loss (≥10%) 18 (9.6) 6 (9.2) 0.926 In this study, the ratio of KFD-affected females to males was Rash 12 (6.4) 3 (4.6) 0.597 [14] 2.9:1. A study by Seo et al, of Korean individuals younger than Myalgia 25 (13.4) 10 (15.4) 0.686 18 years of age, showed no difference in KFD incidence by Arthralgia 12 (6.4) 2 (3.1) 0.311 [20] gender. However, Kang et al reported a female-to-male sex Nausea 10 (5.3) 4 (6.2) 0.807 ratio of KFD of 1.32:1 among Korean children. This difference Headache 16 (8.6) 13 (20.0) 0.013 may be explained by the age differences of the patients between Lymphadenopathy (n, %) these studies, where the median ages were 13.2 and 12.45 years, Involved LN One level cervical LN 179 (94.7) 64 (98.5) 0.200 respectively. In 3 studies on adults, the ratios of affected females [9,10,12] Multiple levels of cervical LNs 176 (93.1) 62 (95.4) 0.517 to males were 4:1, 1.6:1, and 1.26:1, respectively. Extracervical LNs 29 (15.3) 17 (26.2) 0.051 Among our male patients, fever (67%), tenderness on the Size, cm affected LN (32%), and headache (20%) were the most frequent <1 18 (9.5) 3 (4.6) 0.215 symptoms. Although tenderness of the affected site showed no 1–2 116 (61.4) 37 (56.9) 0.527 difference between genders, headache (20%) was more frequent >2 50 (26.5) 24 (36.9) 0.109 in male patients. Fever was also more frequent in males, with Laterality 67% of male patients presenting with fever as an initial symptom. Left 64 (33.9) 18 (22.7) 0.359 However, the total duration of fever was longer in female Right 65 (34.4) 17 (26.2) 0.220 patients, with a mean duration of 13±20.9 days. In a Both 59 (31.2) 30 (46.2) 0.029 [13] retrospective review by Kucukardali et al of 244 KFD patients Onset, mo Less than 1 131 (69.3) 50 (76.9) 0.242 (in which 77% of the patients were female), fever (35%), fatigue 1–2 47 (24.9) 11 (16.9) 0.188 (7%), and joint pain (7%) were the most frequent symptoms. The More than 2 10 (5.3) 4 (6.2) 0.793 most common symptoms of the female patients in this study were Cervical site fever (48%), tenderness of the affected LN (40%), and myalgia Anterior triangle 17 (9.0) 4 (6.2) 0.473 (13%). Arthralgia was present in 6% of the female patients, Posterior triangle 155 (82.0) 54 (83.1) 0.846 similar to the results of the Kucukardali study. Both triangles 17 (9.0) 7 (10.8) 0.673 A study conducted in the United States showed that 83% of Data are expressed as the mean± standard deviation or n (%). AOSD = adult onset Still disease, CKD patients had localized lymphadenopathy, particularly of the = chronic kidney disease, LN = lymph node, MCD = mixed connective tissue disease, SLE = [12] posterior cervical area. In another study of 79 Chinese systemic lupus erythematosus. patients, 97% presented with cervical lymphadenopathy, and Extracervical LN: para-aortic, mesenteric lymph nodes. [21] there was bilateral involvement in 18 (22%) patients. In this P=0.021), and elevated CRP (41 [35%] vs 40 [78.4%], P< 0.001). However, ANA positivity was significantly more frequent Table 3 in female patients (32 [32%] vs 4 [10%], P=0.006) (Table 2). The treatment outcomes of the patients. Regarding the final outcomes, 35.8% of patients showed Female (n= 189) Male (n= 65) P spontaneous clinical improvement, that is, improvement without Treatment (n, %) treatment. Monotherapy, of steroids or nonsteroidal anti- No treatment 67 (35.4) 24 (36.9) 0.831 inflammatory drugs (NSAIDs), was administered to 18% and Steroid 36 (19.0) 10 (15.4) 0.508 33.8% of the patients, respectively; 12% of the patients received NSAIDs 67 (35.4) 19 (29.2) 0.361 both types of treatment. Pathologically proven relapse and Both 19 (10.1) 12 (18.5) 0.074 disease-related mortality occurred more frequently in female Relapse (n, %) 2 (1.1) 0 (0) 0.405 patients, but there was no statistically significant difference Death (n, %) 4 (2.1) 0 (0) 0.237 between males and females (4 [2%] vs 0 [0%], P=0.237) NSAID = nonsteroidal anti-inflammatory drug. (Table 3). 3 Jung et al. Medicine (2017) 96:11 Medicine study, 95.7% of patients presented with cervical lymphadenopa- presented with autoimmune disorders and ANA positivity more thy, most frequently in the posterior cervical triangle. In total, frequently. 46% of male patients had bilateral lymphadenopathy, while this was seen in only 31% of the female patients. The results in this References study are similar to those of previous studies, in which KFD commonly presented as posterior cervical lymphadenopathy, and [1] Fujimoto Y, Kozima Y, Hamaguchi K. Cervical necrotizing lymphade- they show that male patients present with bilateral lymphade- nitis: a new clinicopathological agent. Naika 1972;20:920–7. [2] Kikuchi M. Lymphadenitis showing focal reticulum cell hyperplasia with nopathy more frequently than females. nuclear debris and phagocytosis. Nippon Ketsueki Gakkai Zasshi 1972; In this study, elevated LDH (80%), leukopenia (56%), elevated 35:378–80. CRP (78.4%), and elevated liver enzymes (41%) were the most [3] Yen A, Fearneyhough P, Raimer SS, et al. EBV-associated Kikuchi’s frequent laboratory findings in male patients. Furthermore, histiocytic necrotizing lymphadenitis with cutaneous manifestations. J Am Acad Dermatol 1997;36:342–6. thrombocytopenia, elevated liver enzymes, and LDH are all [4] Hudnall SD, Chen T, Amr S, et al. Detection of human herpesvirus DNA markers of severe inflammation and were seen more frequently in in Kikuchi–Fujimoto disease and reactive lymphoid hyperplasia. Int J [22] male patients. Keogh et al reported a case of a young man Clin Exp Pathol 2008;1:362–8. diagnosed with KFD who developed respiratory failure, [5] Dorfman RF. Histiocytic necrotizing lymphadenitis of Kikuchi and Fujimoto. Arch Pathol Lab Med 1987;111:1026–9. parotidomegaly, and thyroiditis, requiring intensive care unit [6] Anagnostopoulos I, Hummel M, Korbjuhn P, et al. Epstein-Barr virus in management. These findings suggest that KFD in males may be Kikuchi–Fujimoto disease. Lancet 1993;341:893. more commonly associated with severe systemic inflammation [7] Dalton J, Shaw R, Democratis J. Kikuchi–Fujimoto disease. 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Kikuchi–Fujimoto disease: diseases are more frequent in females, which agrees with the [10] clinical and laboratory characteristics and outcome. J Glob Infect Dis results of previous studies. Since KFD and SLE share similar 2014;6:147–50. sex and age profiles, that is, occur more often in young [12] Dorfman RF, Berry GJ. Kikuchi’s histiocytic necrotizing lymphadenitis: [25] females, several studies recommend ANA testing in patients an analysis of 108 cases with emphasis on differential diagnosis. Semin [10,12] Diagn Pathol 1988;5:329–45. initially diagnosed with KFD to exclude concomitant SLE. [13] Kucukardali Y, Solmazgul E, Kunter E, et al. Kikuchi–Fujimoto disease: In this study, the ANA-positive rate was also higher among analysis of 244 cases. Clin Rheumatol 2007;26:50–4. females. [14] Seo JH, Shim HS, Park JJ, et al. A clinical study of histiocytic necrotizing In the majority of patients, KFD is a benign, self-limiting lymphadenitis (Kikuchi’s disease) in children. Int J Pediatr Otorhinolar- [15] disease. Our study results did not differ from those of previous yngol 2008;72:1637–42. [15] Song JY, Lee J, Park DW, et al. Clinical outcome and predictive factors of studies, with more than 35% of the patients showing a recurrence among patients with Kikuchi’s disease. Int J Infect Dis spontaneous resolution without any specific treatment. Death 2009;13:322–6. occurred in 4 female patients, and there was no KFD-related [16] American Diabetes Association. Diagnosis and classification of diabetes mortality in the male patients. No male, and only 2 female, mellitus. Diabetes Care 2010;33(Suppl 1):S62–9. [26] [17] Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke patients experienced a single episode of relapse. Smith et al statistics—2016 update: a report from the American Heart Association. reported a female patient with 4 episodes of recurrent KFD over a Circulation 2016;133:e38–60. period of 18 years. However, as our study only enrolled patients [18] Kirsztajn GM, Filho NS, Draibe SA, et al. Fast reading of the KDIGO with histologically proven KFD, the recurrence rate may have 2012: guidelines for evaluation and management of chronic kidney disease in clinical practice. J Bras Nefrol 2014;36:63–73. been underestimated. [19] Williamson DR, Albert M, Heels-Ansdell D, et al. Thrombocytopenia in There were several limitations to this study. First, it was critically ill patients receiving thromboprophylaxis: frequency, risk conducted retrospectively, and cases without sufficient clinical factors, and outcomes. Chest 2013;144:1207–15. data on the symptoms were excluded. This may have resulted in a [20] Kang HM, Kim JY, Choi EH, et al. Clinical characteristics of severe reduced number of patients with KFD being enrolled. Second, histiocytic necrotizing lymphadenitis (Kikuchi–Fujimoto disease) in children. J Pediatr 2016;171:208–12.e1. only cases that were histopathologically confirmed at initial [21] Kuo TT. Kikuchi’s disease (histiocytic necrotizing lymphadenitis). A diagnosis and recurrence were included. Those patients who were clinicopathologic study of 79 cases with an analysis of histologic very likely to have KFD based solely on their clinical data were subtypes, immunohistology, and DNA ploidy. Am J Surg Pathol not included. Third, a total of 15 patients (12 patients on steroids; 1995;19:798–809. 6 for SLE, 2 for Sjogren disease, 1 for Behçet disease, 2 for AOSD, [22] Keogh MA, Williamson RM, Denaro CP. Kikuchi’s disease associated with parotidomegaly, thyroiditis and a rash in a young man. Aust N Z J 1 for MCD, and 3 patients on NSAIDs due to SLE) already Med 2000;30:633–4. receiving NSAIDs or steroids for treating autoimmune diseases [23] Meyer O, Kahn MF, Grossin M, et al. Parvovirus B19 infection can were included in the study, and this may have interfered with the induce histiocytic necrotizing lymphadenitis (Kikuchi’s disease) associ- evaluation. ated with systemic lupus erythematosus. Lupus 1991;1:37–41. [24] Louis N, Hanley M, Davidson NM. Kikuchi–Fujimoto disease: a report In conclusion, 25.6% of enrolled patients were males, with a of two cases and an overview. J Laryngol Otol 1994;108:1001–4. 2.9:1 female-to-male sex ratio. Male patients showed a distinct [25] Patra A, Bhattacharya SK. SLE developing in a follow-up patient of profile characterized by a higher frequency of fever, headache, Kikuchi’s disease: a rare disorder. J Clin Diagn Res 2013;7:752–3. bilateral lymphadenopathy, and thrombocytopenia, as well as [26] Smith KG, Becker GJ, Busmanis I. Recurrent Kikuchi’s disease. Lancet 1992;340:124. elevated liver enzymes, CRP, and LDH. Female patients

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