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Clinical outcome and predictive factors of recurrence among patients with Kikuchi's disease

  • Joon Young Song
    Affiliations
    Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Korea University Guro Hospital, 97 Guro Dong-Gil, Guro Gu, 152-703 Seoul, Republic of Korea
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  • Jacob Lee
    Affiliations
    Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Korea University Guro Hospital, 97 Guro Dong-Gil, Guro Gu, 152-703 Seoul, Republic of Korea
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  • Dae Won Park
    Affiliations
    Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Korea University Guro Hospital, 97 Guro Dong-Gil, Guro Gu, 152-703 Seoul, Republic of Korea
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  • Jang Wook Sohn
    Affiliations
    Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Korea University Guro Hospital, 97 Guro Dong-Gil, Guro Gu, 152-703 Seoul, Republic of Korea
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  • Sang Il Suh
    Affiliations
    Department of Diagnostic Radiology, Korea University College of Medicine, Seoul, Republic of Korea
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  • In Sun Kim
    Affiliations
    Department of Pathology, Korea University College of Medicine, Seoul, Republic of Korea
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  • Woo Joo Kim
    Affiliations
    Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Korea University Guro Hospital, 97 Guro Dong-Gil, Guro Gu, 152-703 Seoul, Republic of Korea
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  • Min Ja Kim
    Affiliations
    Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Korea University Guro Hospital, 97 Guro Dong-Gil, Guro Gu, 152-703 Seoul, Republic of Korea
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  • Hee Jin Cheong
    Correspondence
    Corresponding author. Tel.: +82 2 2626 3050; fax: +82 2 866 1643.
    Affiliations
    Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Korea University Guro Hospital, 97 Guro Dong-Gil, Guro Gu, 152-703 Seoul, Republic of Korea
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Open ArchivePublished:February 09, 2009DOI:https://doi.org/10.1016/j.ijid.2008.06.022

      Summary

      Objectives

      To evaluate the clinical outcome and predictive factors of recurrence among patients with Kikuchi's disease.

      Methods

      Between January 2001 and December 2006, all patients with Kikuchi's disease were included in the study. Data were collected on co-morbidities, clinical manifestations, and ultrasound/laboratory findings, and the differences were compared between recurrent disease and non-recurrent disease groups.

      Results

      The study included 102 patients with a mean age of 26.7 years. Among these patients, three developed systemic lupus erythematosus during the follow-up period, while two cases were later associated with tuberculosis. Eight patients (7.8%) experienced early relapse and 13 (12.7%) showed late recurrence. Patients with recurrent episodes were more likely to have fever and fatigue with extranodal involvement. Compared to the non-recurrent cases, recurrent cases remained symptomatic for a rather longer duration. The positive rate of the fluorescence anti-nuclear antibody (FANA) test was significantly higher in the recurrent disease group compared to the non-recurrent disease group.

      Conclusions

      Kikuchi's disease took a self-limiting clinical course in most cases, but the recurrence rate found in the present study was higher than that of previous reports. Kikuchi's disease might be a phenotype of diverse disease entities. The prognosis is different according to the underlying cause. The FANA test would be useful in predicting recurrence.

      Keywords

      Introduction

      Kikuchi's disease is a benign, self-limiting disorder, which is characterized by painful regional lymphadenopathy, predominantly in the cervical region, accompanied by fever and night sweats. In addition to the lymphadenopathy, a variable percentage of patients (30–50%) may have low grade fever associated with upper respiratory symptoms.
      • Bosch X.
      • Guilabert A.
      Kikuchi–Fujimoto disease.
      Extranodal involvement is uncommon, but skin rash, hepatitis, arthritis, oral ulcers, and eye involvement have been reported.
      • Bosch X.
      • Guilabert A.
      Kikuchi–Fujimoto disease.
      • Lazzareschi I.
      • Barone G.
      • Ruggiero A.
      • Liotti L.
      • Maurizi P.
      • Larocca L.M.
      • et al.
      Paediatric Kikuchi–Fujimoto disease: a benign cause of fever and lymphadenopathy.
      Although most affected patients recover without serious complications, some of them suffer from recurrent episodes of Kikuchi's disease. A relatively low recurrence rate has been described in 3–7% of cases.
      • Choi J.W.
      • Lee J.H.
      • Chae Y.S.
      • Kim I.
      The clinicopathologic analysis of Kikuchi's lymphadenitis.
      • Takano Y.
      • Saegusa M.
      • Okudaira M.
      Pathologic analyses of non-overt necrotizing type Kikuchi and Fujimoto's disease.
      • Tsang W.Y.
      • Chan J.K.
      • Ng C.S.
      Kikuchi's lymphadenitis. A morphologic analysis of 75 cases with special reference to unusual features.
      Recurrent episodes sometimes cause confusion in clinicians, leading to concerns about the possibility of underlying malignant lymphoma or autoimmune disease; a certain follow-up period is necessary, which is not clearly defined.
      This study was designed to evaluate the clinical course and outcome of Kikuchi's disease. In the case of recurrence, we evaluated the predictive factors of recurrence, making suggestions for the appropriate follow-up period after the initial episode.

      Methods

      Study design

      From 1 January 2001 through 31 December 2006, all patients with pathologically confirmed Kikuchi's disease who attended the Korea University Medical Center were included in the study. Any cases having a follow-up period of less than 12 months were excluded. We reviewed the medical records retrospectively. Kikuchi's disease was defined as any case with regional or generalized lymphadenopathy that showed compatible findings (aggregates of histiocytes and lymphoid cells with abundant karyorrhectic debris) on histology in the absence of clinical and laboratory data suggesting active tuberculosis, lymphoma, or connective tissue disease at initial presentation. Apoptotic plasmacytoid mononuclear cells should be positive for CD68 and myeloperoxidase on immunohistochemical stain. Histopathologic findings were classified into three stages – proliferative, necrotizing, and xanthomatous type – as previously described.
      • Bosch X.
      • Guilabert A.
      • Miquel R.
      • Campo E.
      Enigmatic Kikuchi–Fujimoto disease: a comprehensive review.
      • Kuo T.T.
      Kikuchi's disease (histiocytic necrotizing lymphadenitis). A clinicopathologic study of 79 cases with an analysis of histologic subtypes, immunohistology, and DNA ploidy.
      The proliferative stage consists of various histiocytes, plasmacytoid monocytes, and lymphoid cells with karyorrhectic nuclear fragments, while cellular aggregates with coagulative necrosis indicate the necrotizing stage. Cases with predominant foamy histiocytes are classified as xanthomatous stage regardless of the presence or absence of necrosis. We defined recurrence as redeveloped symptomatic cervical lymphadenitis after at least 1 week from complete clinical resolution, which was stratified into early relapse (within 3 months from disease onset) and late recurrence. As for late recurrence, only biopsy-proven cases were included, while cases were regarded as early relapse based on clinical assessment.

      Data collection

      We collected data on accompanying symptoms, physical findings, co-morbidities, sonographic findings, laboratory results, histological findings, and clinical course. Following this, we compared the differences in demographic, radiological, and laboratory data between the recurrent disease and non-recurrent disease groups.

      Statistical analysis

      Data were analyzed using SPSS 10.0. A p-value of <0.05 was considered statistically significant. The Student's t-test was used to compare quantitative data, and the Chi-square test was used to compare qualitative variables. Multivariate analysis was carried out using a stepwise logistic regression model.

      Results

      Patient characteristics

      The demographic, clinical, and laboratory data at the time of initial diagnosis of Kikuchi's disease are presented in Table 1. Among 137 patients with Kikuchi's disease, 35 patients were excluded from the analysis (26 follow-up loss and nine patients with short-term follow-up). The study included 102 patients (22 male and 80 female subjects) with a mean age of 26.7 years, ranging from 4 to 49 years. The onset of Kikuchi's disease was acute in 60 cases, while 42 cases were subacute (evolved over a period of >2 weeks before visiting the clinic). Patients complained of fever (≥38.0 °C, 73.5%), sore throat (14.7%), cough (11.8%), and fatigue (12.7%). Other manifestations were rare (less than 10%). As for the involved lymph nodes, more than two thirds of patients presented with multiple painful cervical lymphadenopathies, but only four patients showed generalized lymphadenopathy: simultaneous involvement of cervical lymph nodes with axillary (or inguinal) lymph nodes. Diameters of the largest lymph nodes were in the range of 1 to 5.5 cm (mean 1.81 cm). Extranodal involvement was noted among nine patients: skin rash (two cases), oral ulcer (two cases), hepatitis (three cases), arthritis (one case), and meningitis (one case). Patients usually complained of symptoms for about 5–6 weeks (mean 39.1 ± 20.3 days); symptomatic duration was defined as the total period with either systemic symptoms (fever, night sweat, myalgia, arthralgia, etc.) or painful lymphadenopathy. Some cases were related to other medical diseases such as thyroiditis, tuberculosis, systemic lupus erythematosus (SLE), rheumatoid arthritis, or Behcet's disease (Table 1). Except for thyroiditis, these developed later, after the events of Kikuchi's disease, during the follow-up period.
      Table 1Demographic and clinical data of Kikuchi's disease: comparison of epidemiological and clinical features between recurrent and non-recurrent Kikuchi's disease
      Enrolled casesRecurrent cases (N = 21)Non-recurrent cases (N = 81)p-ValueTotal N = 102 (%)
      Age, mean26.1 ± 7.226.9 ± 9.20.7026.7 ± 8.8
      Sex (male:female)5:1617:640.7722 (21.6):80 (78.4)
      Clinical onset
      Acute (<2 weeks of symptoms before visiting any clinics); subacute (≥2 weeks of symptoms before visiting any clinics).
      <0.01
       Acute (<2 weeks)65460 (58.8)
       Subacute (≥2 weeks)152742 (41.2)
      Clinical manifestation
       Fever (≥38.0 °C)19560.0575 (73.5)
       Cough660.0212 (11.8)
       Sore throat3120.9515 (14.7)
       Night sweating360.399 (8.8)
       Weight loss (≥3 kg)240.606 (5.8)
       Fatigue670.0313 (12.7)
       Myalgia340.157 (6.9)
       Headache350.368 (7.8)
      Lymph nodes
       Number (S/M)
      Single/multiple.
      2/199/720.8311 (10.8)/91 (89.2)
       Size (cm)1.90 ± 0.981.78 ± 0.990.961.81 ± 0.99
       Generalized
      Simultaneous involvement of cervical and axillary (or inguinal) lymph nodes.
      220.194 (3.9)
       Tenderness17670.8584 (82.4)
      Extranodal involvement63<0.019 (8.8)
      Comorbidities
      Except for thyroiditis, these developed later, after the events of Kikuchi's disease, during follow-up periods.
      0.78
       Thyroiditis050.585 (4.9)
       Tuberculosis020.982 (2.0)
       Systemic lupus erythematosus300.013 (2.9)
       Rheumatoid arthritis100.211 (1.0)
       Behcet's disease100.212 (2.0)
      Recurrence21 (20.6)
       Early (<3 months)---8 (7.8)
       Late (≥3 months)---13 (12.7)
      Treatment duration (mean days)34.7 ± 23.320.1 ± 13.3<0.0123.0 ± 16.8
      Symptomatic duration (mean days)
      Total period with either systemic symptoms or painful lymphadenopathy.
      54.6 ± 23.735.3 ± 17.5<0.0139.1 ± 20.3
      a Acute (<2 weeks of symptoms before visiting any clinics); subacute (≥2 weeks of symptoms before visiting any clinics).
      b Single/multiple.
      c Simultaneous involvement of cervical and axillary (or inguinal) lymph nodes.
      d Except for thyroiditis, these developed later, after the events of Kikuchi's disease, during follow-up periods.
      e Total period with either systemic symptoms or painful lymphadenopathy.
      With regards to the laboratory data, most patients showed mild leukopenia and an increased level of acute phase reactants (Table 2). Marked leukopenia (leukocyte count less than 4 × 109/l) was observed in 53.5% (53/99 patients). Liver function tests were within the normal range in 97.0% (96/99 patients). As for the lymph node ultrasound, more than 80% were homogeneously enhancing lesions, while central hilar architecture of the lymph node had disappeared (either heterogeneous or hypoechoic) in 12.7% of cases. On histopathologic analysis, necrotizing type was predominant (89.2%).
      Table 2Laboratory and radiological data of Kikuchi's disease: comparison of laboratory and radiological data between recurrent and non-recurrent Kikuchi's disease
      Enrolled casesRecurrent cases (N = 21)Non-recurrent cases (N = 81)p-ValueTotal (N = 102)
      WBC count (× 109/l)3.574 ± 1.3464.271 ± 1.2870.494.077 ± 1.333
      Hemoglobin (g/dl)12.5 ± 1.0215.8 ± 22.430.4814.9 ± 19.1
      Platelet count (× 109/l)202 ± 39215 ± 690.42212 ± 63
      ESR (mm/h)38.6 ± 23.429.4 ± 19.60.0932.1 ± 21.0
      CRP (mg/l)14.4 ± 20.910.2 ± 15.60.4711.7 ± 17.6
      AST (IU/l)25.8 ± 10.931.0 ± 57.60.6929.4 ± 48.2
      ALT (IU/l)21.6 ± 11.831.9 ± 67.20.5128.8 ± 56.3
      ALP (IU/l)63.7 ± 20.580.3 ± 96.40.5175.1 ± 80.9
      Neck sonography (97 cases)0.46
       Preserved echogenic hilum177289 (87.3)
       Loss of echogenic hilum4913 (12.7)
      Biopsy finding0.55
       Necrotizing type207191 (89.2)
       Proliferative type178 (7.9)
       Xanthomatous type033 (2.9)
      WBC, white blood cells; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase.
      Patients were treated with non-steroidal anti-inflammatory drugs (NSAIDs) and prednisolone for symptom relief, which were maintained for 3–4 weeks (mean 23.2 ± 16.9 days). NSAIDs, acetaminophen, steroid, and steroid combined with NSAIDs were administered to 68 patients, 18 patients, six patients, and seven patients, respectively. No medication was prescribed for three patients. There were no significant differences between the recurrent and non-recurrent disease groups with regards to medical therapy.

      Predictive values of recurrent Kikuchi's disease

      Twenty-one patients (20.6%) experienced recurrent episodes of Kikuchi's disease with disease-free intervals ranging from 14 to 1210 days, averaging nine months. Among these, eight cases (7.8%) showed early relapse and 13 cases (12.7%) were late recurrence (Table 1). There was no significant difference in follow-up period between the recurrent and non-recurrent disease groups (mean 25.2 months vs. 27.3 months).
      We tried to identify the predictive factors of recurrence among patients with Kikuchi's disease. On univariate analysis, patients with recurrent episodes were more likely to have fever, cough, and fatigue with frequent extranodal involvement at initial presentation. These cases took a subacute clinical course and remained symptomatic for a rather longer duration (mean 54.6 ± 23.7 vs. 35.3 ± 17.5 days). Laboratory, radiological, and histological findings were indistinguishable between recurrent and non-recurrent groups. On multivariate analysis, the presence of fatigue, extranodal involvement, and long symptomatic duration were statistically significant as predictive factors of recurrence (Table 3). Rheumatologic disease (three cases of SLE, one case of rheumatoid arthritis, and two cases of Behcet's disease) was only noted in the recurrent group, whereas thyroiditis was only noted in the non-recurrent group.
      Table 3Multivariate analysis for the predictive factors of recurrence among patients with Kikuchi's disease
      Enrolled casesRecurrent cases (N = 21)Non-recurrent cases (N = 81)OR (95% CI)
      Clinical onset
      Acute (<2 weeks of symptoms before visiting any clinics); subacute (≥2 weeks of symptoms before visiting any clinics).
      2.94 (0.71–11.36)
       Acute (<2 weeks)654
       Subacute (≥2 weeks)1527
      Fever19562.99 (0.48–18.72)
      Cough662.12 (0.31–14.77)
      Fatigue676.43 (1.25–33.12)
      Extranodal involvement638.29 (1.15–60.06)
      Symptomatic duration
      Total period with either systemic symptoms or painful lymphadenopathy, which persists despite medical treatment.
      54.6 ± 23.735.3 ± 17.51.05 (1.02–1.09)
      OR, odds ratio; CI, confidence interval.
      a Acute (<2 weeks of symptoms before visiting any clinics); subacute (≥2 weeks of symptoms before visiting any clinics).
      b Total period with either systemic symptoms or painful lymphadenopathy, which persists despite medical treatment.
      When we stratified the recurrent disease group into early relapse and late recurrence, there were no remarkable differences in clinical features and laboratory findings between the two subgroups.
      In terms of the fluorescence anti-nuclear antibody (FANA) test, which was performed in 46 cases, positive rates were 53.8% (7/13 cases) in the recurrent disease group and 21.2% (7/33 cases) in the non-recurrent disease group (p < 0.01).

      Discussion

      Kikuchi's disease has been reported worldwide, and it is one of the most common causes of cervical lymphadenitis in Korea.
      • Bosch X.
      • Guilabert A.
      Kikuchi–Fujimoto disease.
      • Kucukardali Y.
      • Solmazgul E.
      • Kunter E.
      • Oncul O.
      • Yildirim S.
      • Kaplan M.
      Kikuchi–Fujimoto disease: analysis of 244 cases.
      According to the report by Kucukardali et al., most cases have been reported from East Asia and the Far East (50%), Europe (27%), and America (7%).
      • Kucukardali Y.
      • Solmazgul E.
      • Kunter E.
      • Oncul O.
      • Yildirim S.
      • Kaplan M.
      Kikuchi–Fujimoto disease: analysis of 244 cases.
      Although infectious etiologies including the Epstein–Barr virus, human herpes virus 6, parainfluenza virus, Toxoplasma gondii, and Yersinia enterocolitica have been suspected, the etiology of Kikuchi's disease still remains unclear.
      • Bosch X.
      • Guilabert A.
      • Miquel R.
      • Campo E.
      Enigmatic Kikuchi–Fujimoto disease: a comprehensive review.
      • Yu H.L.
      • Lee S.S.
      • Tsai H.C.
      • Huang C.K.
      • Chen Y.S.
      • Lin H.H.
      • et al.
      Clinical manifestations of Kikuchi's disease in southern Taiwan.
      • Chiu C.F.
      • Chow K.C.
      • Lin T.Y.
      • Tsai M.H.
      • Shih C.M.
      • Chen L.M.
      Virus infection in patients with histiocytic necrotizing lymphadenitis in Taiwan. Detection of Epstein–Barr virus, type I human T-cell lymphotropic virus, and parvovirus B19.
      • Yen A.
      • Fearneyhough P.
      • Raimer S.S.
      • Hudnall S.D.
      EBV-associated Kikuchi's histiocytic necrotizing lymphadenitis with cutaneous manifestations.
      Likewise, the prognosis of Kikuchi's disease has been poorly evaluated.
      Though previous studies have reported low recurrence rates of Kikuchi's disease in the range of 3% to 7%, we have experienced many recurrent cases in more recent years.
      • Choi J.W.
      • Lee J.H.
      • Chae Y.S.
      • Kim I.
      The clinicopathologic analysis of Kikuchi's lymphadenitis.
      • Takano Y.
      • Saegusa M.
      • Okudaira M.
      Pathologic analyses of non-overt necrotizing type Kikuchi and Fujimoto's disease.
      • Tsang W.Y.
      • Chan J.K.
      • Ng C.S.
      Kikuchi's lymphadenitis. A morphologic analysis of 75 cases with special reference to unusual features.
      For this reason we planned to evaluate the recurrence rate and predictive factors for recurrence in patients with histologically confirmed Kikuchi's disease. In comparison with previous studies, the recurrence rate was remarkably higher in the present study. There are some presumptive reasons. First, the cervical lymphadenopathy clinic is well organized at the Korea University Medical Center, which might have enabled doctors to monitor recurrences more efficiently. Second, there is a chance that the more severe cases were included with pathological confirmation, while the mild cases were excluded due to follow-up loss, thereby overestimating the recurrence rate. Finally, early relapse cases were included, which were clinically diagnosed.
      With the results of the present study, we were able to find some important predictive factors for recurrent Kikuchi's disease: fever, fatigue, extranodal involvement, and long symptomatic duration. Previously, Mohanty et al. reported relapses that occurred within a few weeks after the first episode, while Smith et al. observed relapses that developed over a period of 2 to 10 years after the initial presentation.
      • Lazzareschi I.
      • Barone G.
      • Ruggiero A.
      • Liotti L.
      • Maurizi P.
      • Larocca L.M.
      • et al.
      Paediatric Kikuchi–Fujimoto disease: a benign cause of fever and lymphadenopathy.
      • Mohanty S.K.
      • Arora R.
      • Saha M.
      Kikuchi–Fujimoto disease: an overview.
      • Angel-Moreno A.
      • Hernandez-Cabrera M.
      • Perez-Arellano J.L.
      Kikuchi's disease or Kikuchi's syndrome?.
      • Smith K.G.
      • Becker G.J.
      • Busmanis I.
      Recurrent Kikuchi's disease.
      Contrary to previous reports, recurrences occurred with various disease-free intervals after the initial episode of cervical lymphadenitis. Though therapeutic guidelines are not established, we assumed that early relapse (within 3 months) might have been due to insufficient treatment at the time of initial episode, and late recurrence associated with underlying autoimmune (connective tissue) diseases. Though it was statistically insignificant, due to the small number of cases, connective tissue diseases were considered to be associated with recurrence; the positive rate of FANA was significantly higher in the recurrent cases compared to the non-recurrent cases. Previously, Kucukardali et al. reported that FANA positivity (23.4% vs. 3%) and SLE association rates (28% vs. 9%) were significantly higher in East Asia and the Far East compared to those in Europe.
      • Kucukardali Y.
      • Solmazgul E.
      • Kunter E.
      • Oncul O.
      • Yildirim S.
      • Kaplan M.
      Kikuchi–Fujimoto disease: analysis of 244 cases.
      However, there was a chance that recurrent disease with positive FANA might simply reflect the overlap between SLE and Kikuchi's disease. Cervical lymphadenitis could be the initial presentation of SLE in some patients, which is supported by the finding that three among 21 patients with ‘recurrent’ disease developed SLE in the follow-up period, in contrast to none among 81 patients with ‘non-recurrent’ disease. A prospective cohort study is required to clarify this point. On the other hand, self-limiting thyroiditis was only found in the non-recurrent cases. We tried to analyze the differences between early relapse and late recurrence, but no contributing factor was identified, which would be the limitation of a retrospective study.
      In conclusion, Kikuchi's disease took a self-limiting clinical course in most cases, but the recurrence rate was higher compared to that of previous reports. Kikuchi's disease might be a phenotype of diverse disease entities. The prognosis is different according to the causative illness. The FANA test would be useful in predicting the patient's prognosis.
      Conflict of interest: No conflict of interest to declare.

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