- Email: [email protected]
Clinical Characteristics of Severe Histiocytic Necrotizing Lymphadenitis (Kikuchi-Fujimoto Disease) in Children
Clinical Characteristics of Severe Histiocytic Necrotizing Lymphadenitis (Kikuchi-Fujimoto Disease) in Children Hyun Mi Kang, MD1,2,3, Ji Young Kim, MD4, Eun Hwa Choi, MD1,2, Hoan Jong Lee, MD1,2, Ki Wook Yun, MD1,2, and Hyunju Lee, MD1,3 Objectives To analyze the clinical characteristics of children with Kikuchi-Fujimoto disease focusing on cases with prolonged fever. Study design This was a retrospective study of children diagnosed with Kikuchi-Fujimoto disease from March 2003 to February 2015 in South Korea. Electronic medical records were searched for clinical and laboratory manifestations. Results Among 86 histopathologically confirmed cases, the mean age was 13.2 (SD 3.1) years, and male to female ratio was 1:1.32. Cervical lymph node enlargement, found in 85 of the patients (99%), was predominantly unilateral in 64 (75%), and involved the cervical lymph node level V in 67 (81%). Fever was present in 76% of the cases, with a median duration of 9 days (IQR 0.25-17.0). Multivariate analysis revealed that a high fever peak $39.0 C (P = .010) and presentation with $2 systemic symptoms other than fever (P = .027) were factors that were significantly associated with longer fever duration. As the size of the largest lymph node’s short diameter increased, the fever duration increased (P = .015). Leukopenia (P = .022) also had a significant association with a longer fever duration. Patients with sonographic findings of conglomerated enlarged lymph nodes had a longer median duration of fever compared with those with separate enlarged lymph nodes (11 vs 4.5 days, P = .019). Conclusions Patients with high fever, more systemic symptoms, leukopenia, and larger lymph nodes with a conglomerated distribution may benefit from early recognition and selective consideration of corticosteroid therapy. (J Pediatr 2016;-:---).
H
istiocytic necrotizing lymphadenitis, also known as Kikuchi-Fujimoto disease (KFD), is characterized by regional lymphadenopathy and fever. It is a self-limiting disease of unknown etiology, endemic in Asia, and usually has a benign course and low recurrence rate. KFD has a wide clinical spectrum ranging from absence of systemic symptoms to prolonged fever and significant symptoms such as night sweats, myalgia, arthralgia, weight loss, and hemophagocytic lymphohistiocytosis.1-7 KFD is a rare form of lymphadenitis described in both adults and children.8-11 KFD is confirmed by histopathologic findings of lymph node biopsy.12 Early diagnosis is important in order to avoid unnecessary evaluations for various other causes of cervical lymphadenopathy.5 However, biopsy often is delayed because of the risks involved with the procedure, the need for admission or sedation in children, or simply because of waiting for the lymphadenitis to resolve. The delay in diagnosis along with prolonged systemic symptoms leads to frequent hospital visits, long admission periods, or missed schooling. Immune modulating drugs such as corticosteroids have been used in these patients, which may shorten the clinical course.13-15 However, there are no guidelines for corticosteroid use, and because KFD generally has a self-limiting course, drug misuse and overuse are concerns. The primary aim of this study was to investigate the clinical characteristics of children with KFD to assess factors associated with a more severe clinical course, focusing on patients with prolonged fever.
Methods This was a retrospective study of patients <19 years old who were diagnosed with KFD between March 2003 and February 2015 at Seoul National University Bundang Hospital, a tertiary care referral hospital located in the outskirts of Seoul. KFD was diagnosed when all of the following criteria were fulfilled: (1) systemic symptoms or physical findings compatible with KFD (systemic symptom such as fever, headache, dizziness, loss of appetite, fatigue, myalgia, gastrointesFrom the Department of Pediatrics, Seoul National tinal disturbance, and arthralgia and physical findings such as lymph node University College of Medicine; Department of Pediatrics, Seoul National University Children’s Hospital, enlargement, hepatomegaly, splenomegaly, and rash); (2) exclusion of any other Seoul, Republic of Korea; and Departments of causes of lymphadenopathy; and (3) histology for lymph node biopsy showing Pediatrics, and Radiology, Seoul National University 1
2
3
4
Bundang Hospital, Seongnam, Republic of Korea The authors declare no conflicts of interest.
CT KFD
Computed tomography Kikuchi-Fujimoto disease
0022-3476/$ - see front matter. Copyright ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.12.064
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THE JOURNAL OF PEDIATRICS
nodal paracortical and cortical lesions composed of karyorrhexis, nuclear debris, and infiltration of histiocytes, lymphoid cells, and plasmacytoid monocytes.16-19 The electronic medical records of the patients were reviewed. Data collected included age, presenting symptoms, laboratory test results, biopsy methods, histologic findings, treatment, and outcome including duration of symptoms. The ultrasound or computed tomography (CT) images were reviewed by a single pediatric radiologist for uniform measurements of the short and long diameter of the largest lymph nodes, distribution of the enlarged lymph nodes, and other imaging characteristics of the enlarged nodes specific to KFD. The duration of fever was defined as the number of days for which the patient had a body temperature of $38.0 C with an interval of <24 hours between each episode of fever. All cases with splenomegaly and hepatomegaly were confirmed via abdomen ultrasonography or CT. Statistical Analyses Multivariate logistic regression analysis was performed to identify factors associated with the duration of fever using the selection method (backward selection) for variables that were statistically significant in the univariate analysis. Statistical analyses were performed using the R v 3.2.1. (R Foundation for statistical computing, Vienna, Austria). Fisher exact test was used to compare categorical variables for analyzing the clinical characteristics of patients according to the distribution of the enlarged lymph nodes. Continuous variables for treatment response were compared by the MannWhitney U test. SPSS v 21.0 (SPSS Inc, Chicago, Illinois) was used to perform statistical analyses. All the statistical tests performed were 2-tailed and a P value of #.05 was considered significant.
Results During this 12-year period, a total of 86 patients <19 years of age fulfilled the case definition of KFD. The mean age was 13.2 years old (SD 3.1), and the age range was 5-18.8 years (Table I and Figure 1; Figure 1 available at www.jpeds.com). The male to female ratio was 1:1.32, and seasonal distribution showed that the onset of KFD was more common during the winter (34%, n = 29) than other seasons of the year (Figure 2; available at www.jpeds.com). Lymph node biopsies were performed on median day 10 (IQR 5-19.5 days) of illness. Table I shows general characteristics of patients with KFD. Of 86 cases, 85 (99%) had cervical lymph node enlargement. One patient did not come to attention with cervical lymphadenitis but had multiple axillary, inguinal, and retroperitoneal nodes enlarged. The majority of the patients (64, 75%) had unilateral cervical node involvement. Lymph node tenderness was present in 53 (62%). Fever was present in 65 of the patients (76%), of whom 40 (47%) had a fever of $39.0 C. The median duration of fever was 9 days (IQR 0.25-17.0). Furthermore, 32 of the patients (37%) had prolonged fever of $2 weeks, and 7 of the patients (8%) had a fever of $4 weeks. 2
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Table I. General characteristics of children with KFD No. of cases (%), N = 86 Age, y, mean (SD) Female Lymphadenopathy Cervical Axillary Inguinal Mesenteric Retroperitoneal Systemic symptoms Fever Loss of appetite Fatigue Headache Night sweats Arthralgia Myalgia Physical findings Rash Splenomegaly Oral mucosal ulceration Uveitis Parotitis Thyroiditis Pericardial effusion Laboratory findings* Hemoglobin (mg/dL) WBC (4 103/mm3) ANC (103/mm3) Platelet (103/mm3) ESR (mm/h) CRP (mg/dL) AST (mg/dL) ALT (mg/dL) Ferritin (mg/dL) LDH (mg/dL)
13.2 (3.1) 49 (57) 85 (99) 6 (7) 5 (6) 2 (2) 1 (1) 65 (76) 25 (29) 21 (24) 21 (24) 16 (19) 11 (13) 8 (9) 16 (19) 9 (10) 5 (6) 4 (5) 4 (5) 2 (2) 1 (1) (mean SD, range) 12.1 1.3 (9.1-15.7) 3.4 1.7 (1.1-9.4) 1.5 1.0 (0.3-6.9) 193 57 (69-337) 31 20 (4-116) 2.7 3.4 (0.01-16.9) 60 77 (16-479) 67 108 (8-728) 480 565 (54-2000) 479 300 (168-1970)
ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; LDH, lactate dehydrogenase; WBC, white blood cell count. *Patients whose laboratory findings were unavailable of analysis were excluded: total (N = 73).
Overall, 42% (n = 36) of the patients had >2 systemic symptoms other than fever, and 28% (n = 24) had >3 systemic symptoms. Of these, loss of appetite, fatigue, and headache were predominant. The most common extranodal manifestations included rash, splenomegaly, and oral mucosal ulceration, but none occurred in <20% of patients. Of the 76 patients who had laboratory findings available for analysis, 35 (46%) had anemia (Hb <11 mg/dL), 57 (74%) had leukopenia (white blood cell count <4 103/ mm3), 26 (34%) had neutropenia (absolute neutrophil count <1 103/mm3), and 19 (25%) had thrombocytopenia (platelet <150 103/mm3). Image Findings Ultrasound or CT images were unavailable for re-evaluation in 3 patients. Of the 83 patients with images of enlarged lymph nodes, 78 (94%) were ultrasound images and 5 (6%) were CT images. All patients had multiple enlarged lymph nodes, and the most common area of involvement was the posterior triangle at cervical lymph node level V (n = 67, 81%). The mean short and long diameters of the largest lymph node were 9.4 mm (range 3-22 mm) and 19.0 mm (range 10-35 mm), respectively. Also, 39% Kang et al
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ORIGINAL ARTICLES node enlargement (P = .018), and splenomegaly (P = .005) were factors associated with a longer fever duration. As the short diameter of the largest lymph node increased, the fever duration also increased significantly (P = .006). Leukopenia (P < .001), neutropenia (P = .001), elevated erythrocyte sedimentation rate (P = .002), ferritin (P = .006), aspartate aminotransferase (P = .010), and alanine aminotransferase (P = .031) were associated with a longer fever duration (Table III). In a multivariate analysis, high fever peak $39.0 C (P = .010) and presentation with $2 systemic symptoms other than fever (P = .027) were significantly associated with longer fever duration. As the size of the largest lymph node’s short diameter increased, the fever duration increased (P = .015). Leukopenia (P = .022) also had a significant association with a longer fever duration (Table III). Although fever duration did not increase significantly depending on the distribution of the enlarged lymph nodes (P = .242), the presence of fever was significantly associated with conglomerated distribution (P = .002) (Table IV). Patients with conglomerated lymphadenopathy had a longer median duration of fever than those with a separated distribution (11 vs 4.5 days, P = .019), and a higher fever peak ($39 C) (65% vs 27%, P = .001). Also, patients with conglomerated nodes had more systemic symptoms (52% vs 30%, P = .047), as well as abnormal laboratory findings such as leukopenia (89% vs 53%, P = .001) (Table IV).
Table II. Image findings of children diagnosed with KFD No. of cases (%) (N = 83)* Diameter of the largest lymph node Short (mm), mean (SD) Long (mm), mean (SD) Short $10 mm Long $20 mm Bilateral involvement Conglomerated distribution Increased perinodal fat echogenicity
9.4 (3.3) 19.0 (5.5) 32 (39) 36 (43) 21 (26) 45 (54) 70 (84)
*Patients without image findings available for re-evaluation were excluded.
(n = 32) had lymph nodes $10 mm (short diameter) and 43% (n = 36) had lymph nodes $20 mm (long diameter). Increased perinodal fat echogenicity was a characteristic finding, observed in 70 patients’ ultrasound images (84%; Table II). Two distinct types of node distribution were observed: separate (n = 37, 45%) vs conglomerated (n = 46, 54%). Patients with conglomerated nodes had a significantly longer short diameter of the largest lymph node compared with those with separate enlarged lymph node (10.1 mm vs 8.6 mm, P = .043; Table II). Factors Associated with a More Severe Clinical Course Univariate analysis showed that a high fever peak (P < .001), $2 systemic symptoms other than fever (P < .001), bilateral
Table III. Factors associated with longer fever duration in children diagnosed with KFD Univariate analysis
Age at diagnosis Sex Female Male Need for admission Symptoms Fever peak $39.0 C $2 systemic symptoms other than fever Signs (physical findings) Bilateral Lymph node tenderness Hepatomegaly Splenomegaly Rash Diameter of the largest lymph node Short (mm) Long (mm) Laboratory findings* Anemia Leukopenia Neutropenia Thrombocytopenia ESR $30 mm/h CRP $5 mg/dL Ferritin $500 mg/dL LDH $500 mg/dL AST >40 mg/dL ALT >40 mg/dL
Multivariate analysis
Coefficient b
SE
P value
0.215
0.368
.561
1.120 10.022
2.409 2.114
.643 <.001
10.232 8.440
2.084 2.207
<.001 <.001
6.317 0.920 7.873 10.514 5.597
2.622 2.463 7.620 3.598 2.923
.018 .710 .305 .005 .059
0.980 0.156
0.347 0.216
.006 .472
12.129 10.603 8.258 7.577 8.129 2.121 9.884 4.067 6.859 5.916
6.158 2.570 2.457 7.638 2.557 3.291 3.458 5.340 2.573 2.679
.053 <.001 .001 .325 .002 .521 .006 .456 .010 .031
Coefficient b
SE
P value
6.017 5.024
2.279 2.229
.010 .027
5.492
3.269
.097
0.767
0.308
.015
7.885
3.336
.022
4.159
2.763
.139
4.756
2.687
.083
Reference
Definition: anemia (Hb <11 mg/dL); leukopenia (WBC <4.0 103/mm3); neutropenia (ANC <1.0 103/mm3); thrombocytopenia (platelet <150 103/mm3). Patients without radiographic images or fever duration available were excluded: total (N = 81). *Patients whose laboratory findings were unavailable of analysis were excluded: total (N = 73).
Clinical Characteristics of Severe Histiocytic Necrotizing Lymphadenitis (Kikuchi-Fujimoto Disease) in Children
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Table IV. Clinical characteristics of patients diagnosed with KFD according to the distribution of the enlarged lymph nodes No. of cases (%) Several separated Conglomerated P (N = 37) (N = 46) value* Symptoms Fever Duration of fever, median d (IQR) Fever $39 C $2 systemic symptoms other than fever Signs (physical findings) Bilateral Lymph node tenderness Hepatomegaly Splenomegaly Rash Oral mucosal ulceration Laboratory findingsz Anemia Leukopenia Neutropenia Thrombocytopenia ESR $30 mm/h CRP $5 mg/dL Ferritin $500 mg/dL LDH $500 mg/dL AST >40 mg/dL ALT >40 mg/dL
22 (59) 4.5 (0-17) 10 (27) 11 (30)
41 (89) 11 (7-18) 30 (65) 24 (52)
.002 .019† .001 .047
6 (16) 20 (54) 1 (3) 3 (8) 6 (16) 1 (3)
15 (33) 32 (70) 1 (2) 6 (13) 10 (22) 4 (9)
.127 .175 1 .725 .586 .375
11 (37) 16 (53) 9 (24) 5 (17) 8 (27) 4 (13) 1 (3) 4 (13) 7 (23) 7 (23)
23 (52) 39 (89) 16 (36) 13 (30) 23 (52) 9 (20) 9 (20) 13 (30) 15 (34) 14 (32)
.237 .001 .624 .273 .033 .541 .042 .159 .438 .6
Definition: anemia (Hb <11 mg/dL); leukopenia (WBC <4.0 103/mm3); neutropenia (ANC <1.0 103/mm3); thrombocytopenia (platelet <150 103/mm3). Patients without radiographic images available for re-evaluation were excluded from the analysis: total (N = 83). *Fisher exact test, Several separated vs conglomerated. †Mann-Whitney U-test, several separated vs conglomerated. zPatients whose lab findings were unavailable of analysis were excluded: total (N = 74); Several separated (N = 30), conglomerated (N = 44).
Treatment and Outcome Two-thirds of the 58 patients were given oral (n = 45) or parenteral (n = 13) antibiotics prior to confirming the diagnosis of KFD, of which oral amoxicillin-clavulanate (36%) was the most commonly prescribed antibiotic. Nonsteroidal anti-inflammatory agents were administered in 44 of the patients (51%) for managing systemic symptoms after the diagnosis of KFD was confirmed. Although a majority of the patients’ symptoms improved with conservative management, oral prednisolone was administered in 24 of the patients (28%), and of these, 16 (67%) had a prolonged fever lasting $2 weeks prior to steroid administration (P = .001). The following dosages of oral prednisolone were administered: 1.5 mg/kg/d in 4%, 1 mg/kg/d in 67%, 0.5 mg/kg/ d in 29% of patients. The duration of corticosteroid treatment was #7 days in 63% of the patients, whereas 38% were administered corticosteroids for 8-12 days. Of 19 patients with the time to defervescence after initiating corticosteroid treatment recorded, 15 (79%) had defervescence within 24 hours, 3 (16%) within 48 hours, and only 1 patient required up to 72 hours. Although several factors were considered when initiating corticosteroid treatment, prolonged fever after histopatho4
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logic confirmation (n = 17; 71%) was the most common. Other reasons included large neck mass (n = 9), aggravating pancytopenia (n = 8), extreme fatigue (n = 1), and recurrence (n = 1). Overall, recurrence occurred in 10% (n = 9) of the patients. The duration of fever was not associated with recurrence (only 2 of 9 had prolonged fever), and a male predominance was observed (n = 8; 88%).
Discussion KFD has a wide clinical spectrum and although generally is self-limiting, some patients suffer more than others from prolonged systemic symptoms during the course of the disease.4,5,10 In this study, we found that KFD occurred mostly in the early adolescence, and as previously reported in other studies on children, cervical lymph node enlargement and fever were predominating symptoms.8,9 Most, but not all, patients had cervical lymph node involvement, and similar to other studies, the absence of fever did not exclude KFD.5 Patients included in this study had shorter lengths of illnesses compared with other studies,6 with a median of 9 days of fever. A possible reason for this difference is that KFD encompasses a wide spectrum of disease severity, and patients from mild to severe clinical spectrums were included. Enlarged lymph nodes in the posterior triangle at cervical lymph node level V were most commonly involved and lymph node tenderness was observed in more than two-thirds of patients. Although KFD is known to be a self-limiting disease, symptoms can persist over weeks as shown in our study. During the prolonged course of illness, children suffer from decreased school performance, numerous visits to clinics, admissions to the hospital, and/or acute deterioration of health. Many studies have reported the dramatic effects of corticosteroids, which are administered as immune modulators in patients that suffer from prolonged fever.13-15 In this study, patients with a higher fever peak that reached above 39 C, and those who had more systemic symptoms such as loss of appetite, fatigue, and headache had significantly longer fever duration. The short diameter of the largest lymph node, as well as leukopenia, which was previously reported to be significantly associated with prolonged fever in KFD,9 were significantly associated with longer fever duration in our study. Considering the self-limiting nature of the disease and the potential adverse effects of corticosteroids, treatment should be considered in selected cases, potentially using factors we identified as significantly associated with a more severe and protracted clinical course. There are numerous causes of cervical lymphadenopathy, and understanding the characteristic sonographic findings of KFD aids in the differential diagnosis. In KFD, nodes typically show focal low attenuation and perinodal infiltration.20 A study on 175 adults with KFD suggested that perinodal echogenicity is a characteristic finding in KFD.21 Likewise, in this study, a majority of the patients had perinodal fat echogenicity. Kang et al
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We characterized 2 distinct distribution types of the enlarged nodes, conglomerated and separate. In our study, patients with conglomerated distribution had a significantly more severe disease course, with longer fever duration, higher fever peak, and more systemic accompanying symptoms. Leukopenia as well as elevated erythrocyte sedimentation rate and ferritin level also was more common in these patients. A major limitation to this study was its retrospective nature, and the possibility of incomplete medical records. However, all patients included in this study had recordings of their physical findings and clinical symptoms, and only patients with fever peaks and duration recorded in the electronic medical records were included in the analysis on fever duration and lymph node distribution. Another limitation was that the patients were all from a single center. However, because it was a single center study, there was an advantage that the physicians, radiologists, and surgeons involved in treating the cases were relatively uniform in assessments and management, thus reducing biases. KD, in general, is a self-limiting disease; however, some patients have a more severe and prolonged course. Patients with high fever, more systemic symptoms, leukopenia, and larger lymph nodes with a conglomerated distribution may benefit from early recognition so that benefits and risks of corticosteroid therapy can be selectively weighed. n Submitted for publication Aug 21, 2015; last revision received Oct 27, 2015; accepted Dec 23, 2015. Reprint requests: Hyunju Lee, MD, Department of Pediatrics, Seoul National University Bundang Hospital, 82, Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, Republic of Korea 463-707. E-mail: mdopd@ hanmail.net or [email protected]
References 1. Kim YM, Lee YJ, Nam SO, Park SE, Kim JY, Lee EY. Hemophagocytic syndrome associated with Kikuchi’s disease. J Korean Med Sci 2003; 18:592-4. 2. Chen JS, Chang KC, Cheng CN, Tsai WH, Su IJ. Childhood hemophagocytic syndrome associated with Kikuchi’s disease. Haematologica 2000;85:998-1000. 3. Lin YW, Horiuchi H, Ueda I, Nambu M. Recurrent hemophagocytic lymphohistiocytosis accompanied by Kikuchi’s disease. Leuk Lymphoma 2007;48:2447-51.
4. Dorfman RF, Berry GJ. Kikuchi’s histiocytic necrotizing lymphadenitis: an analysis of 108 cases with emphasis on differential diagnosis. Semin Diagn Pathol 1988;5:329-45. 5. Kucukardali Y, Solmazgul E, Kunter E, Oncul O, Yildirim S, Kaplan M. Kikuchi-Fujimoto disease: analysis of 244 cases. Clin Rheumatol 2007; 26:50-4. 6. Feder HM Jr, Liu J, Rezuke WN. Kikuchi disease in Connecticut. J Pediatr 2014;164:196-200.e1. 7. Sunghoon C, Park S, Lee K, Song J, Han M, Choi Y, et al. Clinical characteristics of Kikuchi disease in children. Pediatr Infect Vaccine 2007;14: 129-35. 8. Seo JH, Shim HS, Park JJ, Jeon SY, Kim JP, Ahn SK, et al. A clinical study of histiocytic necrotizing lymphadenitis (Kikuchi’s disease) in children. Int J Pediatr Otorhinolaryngol 2008;72:1637-42. 9. Chuang CH, Yan DC, Chiu CH, Huang YC, Lin PY, Chen CJ, et al. Clinical and laboratory manifestations of Kikuchi’s disease in children and differences between patients with and without prolonged fever. Pediatr Infect Dis J 2005;24:551-4. 10. Lee KY, Yeon YH, Lee BC. Kikuchi-Fujimoto disease with prolonged fever in children. Pediatrics 2004;114:e752-6. 11. Lin HC, Su CY, Huang SC. Kikuchi’s disease in Asian children. Pediatrics 2005;115:e92-6. 12. Tsang WY, Chan JK. Fine-needle aspiration cytologic diagnosis of Kikuchi’s lymphadenitis. A report of 27 cases. Am J Clin Pathol 1994;102:4548. 13. Yoshioka K, Miyashita T, Nakamura T, Inoue T, Yamagami K. Treatment of histiocytic necrotizing lymphadenitis (Kikuchi’s disease) with prolonged fever by a single course of methylprednisolone pulse therapy without maintenance therapy: experience with 13 cases. Intern Med 2010;49:2267-70. 14. Jang YJ, Park KH, Seok HJ. Management of Kikuchi’s disease using glucocorticoid. J Laryngol Otol 2000;114:709-11. 15. Yalcin S, Toprak SK, Erismis B, Altundag O, Ozdemir H, Topcuoglu N. Management of Kikuchi-Fujimoto disease using glucocorticoid: a case report. Case Rep Med 2011;2011:230840. 16. Fujimoto Y, Kojima Y, Yamaguchi K. Cervical subacute necrotizing lymphadenitis. Naika 1972;30:920-7. 17. Feller AC, Lennert K, Stein H, Bruhn HD, Wuthe HH. Immunohistology and aetiology of histiocytic necrotizing lymphadenitis. Report of three instructive cases. Histopathology 1983;7:825-39. 18. Facchetti F, de Wolf-Peeters C, Van Den Oord JJ, De Vos R, Desmet VJ. Plasmacytoid monocytes (so-called plasmacytoid T-cells) in Kikuchi’s lymphadenitis. An immunohistologic study. Am J Clin Pathol 1989;92: 42-50. 19. Bosch X, Guilabert A, Miquel R, Campo E. Enigmatic Kikuchi-Fujimoto disease a comprehensive review. Am J Clin Pathol 2004;122:141-52. 20. Kwon SY, Kim TK, Kim YS, Lee KY, Lee NJ, Seol HY. CT findings in Kikuchi disease: analysis of 96 cases. AJNR Am J Neuroradiol 2004;25: 1099-102. 21. Yoo JL, Suh SI, Lee YH, Seo HS, Kim KM, Shin BK, et al. Gray scale and power Doppler study of biopsy-proven Kikuchi disease. J Ultrasound Med 2011;30:957-63.
Clinical Characteristics of Severe Histiocytic Necrotizing Lymphadenitis (Kikuchi-Fujimoto Disease) in Children
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No. of patients
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12 10 8 6 4 2 0 5
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11 12 13 Age (years)
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Figure 1. Age distribution of the patients diagnosed with KFD.
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No. of patients
30 25 20 15 10 5 0 Spring
Summer Fall Season
Winter
Figure 2. Seasonal distribution of the patients diagnosed with KFD (Spring: March, April, May; Summer: June, July, August; Fall: September, October, November; Winter: December, January, February). 5.e1
Kang et al
H
istiocytic necrotizing lymphadenitis, also known as Kikuchi-Fujimoto disease (KFD), is characterized by regional lymphadenopathy and fever. It is a self-limiting disease of unknown etiology, endemic in Asia, and usually has a benign course and low recurrence rate. KFD has a wide clinical spectrum ranging from absence of systemic symptoms to prolonged fever and significant symptoms such as night sweats, myalgia, arthralgia, weight loss, and hemophagocytic lymphohistiocytosis.1-7 KFD is a rare form of lymphadenitis described in both adults and children.8-11 KFD is confirmed by histopathologic findings of lymph node biopsy.12 Early diagnosis is important in order to avoid unnecessary evaluations for various other causes of cervical lymphadenopathy.5 However, biopsy often is delayed because of the risks involved with the procedure, the need for admission or sedation in children, or simply because of waiting for the lymphadenitis to resolve. The delay in diagnosis along with prolonged systemic symptoms leads to frequent hospital visits, long admission periods, or missed schooling. Immune modulating drugs such as corticosteroids have been used in these patients, which may shorten the clinical course.13-15 However, there are no guidelines for corticosteroid use, and because KFD generally has a self-limiting course, drug misuse and overuse are concerns. The primary aim of this study was to investigate the clinical characteristics of children with KFD to assess factors associated with a more severe clinical course, focusing on patients with prolonged fever.
Methods This was a retrospective study of patients <19 years old who were diagnosed with KFD between March 2003 and February 2015 at Seoul National University Bundang Hospital, a tertiary care referral hospital located in the outskirts of Seoul. KFD was diagnosed when all of the following criteria were fulfilled: (1) systemic symptoms or physical findings compatible with KFD (systemic symptom such as fever, headache, dizziness, loss of appetite, fatigue, myalgia, gastrointesFrom the Department of Pediatrics, Seoul National tinal disturbance, and arthralgia and physical findings such as lymph node University College of Medicine; Department of Pediatrics, Seoul National University Children’s Hospital, enlargement, hepatomegaly, splenomegaly, and rash); (2) exclusion of any other Seoul, Republic of Korea; and Departments of causes of lymphadenopathy; and (3) histology for lymph node biopsy showing Pediatrics, and Radiology, Seoul National University 1
2
3
4
Bundang Hospital, Seongnam, Republic of Korea The authors declare no conflicts of interest.
CT KFD
Computed tomography Kikuchi-Fujimoto disease
0022-3476/$ - see front matter. Copyright ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.12.064
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nodal paracortical and cortical lesions composed of karyorrhexis, nuclear debris, and infiltration of histiocytes, lymphoid cells, and plasmacytoid monocytes.16-19 The electronic medical records of the patients were reviewed. Data collected included age, presenting symptoms, laboratory test results, biopsy methods, histologic findings, treatment, and outcome including duration of symptoms. The ultrasound or computed tomography (CT) images were reviewed by a single pediatric radiologist for uniform measurements of the short and long diameter of the largest lymph nodes, distribution of the enlarged lymph nodes, and other imaging characteristics of the enlarged nodes specific to KFD. The duration of fever was defined as the number of days for which the patient had a body temperature of $38.0 C with an interval of <24 hours between each episode of fever. All cases with splenomegaly and hepatomegaly were confirmed via abdomen ultrasonography or CT. Statistical Analyses Multivariate logistic regression analysis was performed to identify factors associated with the duration of fever using the selection method (backward selection) for variables that were statistically significant in the univariate analysis. Statistical analyses were performed using the R v 3.2.1. (R Foundation for statistical computing, Vienna, Austria). Fisher exact test was used to compare categorical variables for analyzing the clinical characteristics of patients according to the distribution of the enlarged lymph nodes. Continuous variables for treatment response were compared by the MannWhitney U test. SPSS v 21.0 (SPSS Inc, Chicago, Illinois) was used to perform statistical analyses. All the statistical tests performed were 2-tailed and a P value of #.05 was considered significant.
Results During this 12-year period, a total of 86 patients <19 years of age fulfilled the case definition of KFD. The mean age was 13.2 years old (SD 3.1), and the age range was 5-18.8 years (Table I and Figure 1; Figure 1 available at www.jpeds.com). The male to female ratio was 1:1.32, and seasonal distribution showed that the onset of KFD was more common during the winter (34%, n = 29) than other seasons of the year (Figure 2; available at www.jpeds.com). Lymph node biopsies were performed on median day 10 (IQR 5-19.5 days) of illness. Table I shows general characteristics of patients with KFD. Of 86 cases, 85 (99%) had cervical lymph node enlargement. One patient did not come to attention with cervical lymphadenitis but had multiple axillary, inguinal, and retroperitoneal nodes enlarged. The majority of the patients (64, 75%) had unilateral cervical node involvement. Lymph node tenderness was present in 53 (62%). Fever was present in 65 of the patients (76%), of whom 40 (47%) had a fever of $39.0 C. The median duration of fever was 9 days (IQR 0.25-17.0). Furthermore, 32 of the patients (37%) had prolonged fever of $2 weeks, and 7 of the patients (8%) had a fever of $4 weeks. 2
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Table I. General characteristics of children with KFD No. of cases (%), N = 86 Age, y, mean (SD) Female Lymphadenopathy Cervical Axillary Inguinal Mesenteric Retroperitoneal Systemic symptoms Fever Loss of appetite Fatigue Headache Night sweats Arthralgia Myalgia Physical findings Rash Splenomegaly Oral mucosal ulceration Uveitis Parotitis Thyroiditis Pericardial effusion Laboratory findings* Hemoglobin (mg/dL) WBC (4 103/mm3) ANC (103/mm3) Platelet (103/mm3) ESR (mm/h) CRP (mg/dL) AST (mg/dL) ALT (mg/dL) Ferritin (mg/dL) LDH (mg/dL)
13.2 (3.1) 49 (57) 85 (99) 6 (7) 5 (6) 2 (2) 1 (1) 65 (76) 25 (29) 21 (24) 21 (24) 16 (19) 11 (13) 8 (9) 16 (19) 9 (10) 5 (6) 4 (5) 4 (5) 2 (2) 1 (1) (mean SD, range) 12.1 1.3 (9.1-15.7) 3.4 1.7 (1.1-9.4) 1.5 1.0 (0.3-6.9) 193 57 (69-337) 31 20 (4-116) 2.7 3.4 (0.01-16.9) 60 77 (16-479) 67 108 (8-728) 480 565 (54-2000) 479 300 (168-1970)
ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; LDH, lactate dehydrogenase; WBC, white blood cell count. *Patients whose laboratory findings were unavailable of analysis were excluded: total (N = 73).
Overall, 42% (n = 36) of the patients had >2 systemic symptoms other than fever, and 28% (n = 24) had >3 systemic symptoms. Of these, loss of appetite, fatigue, and headache were predominant. The most common extranodal manifestations included rash, splenomegaly, and oral mucosal ulceration, but none occurred in <20% of patients. Of the 76 patients who had laboratory findings available for analysis, 35 (46%) had anemia (Hb <11 mg/dL), 57 (74%) had leukopenia (white blood cell count <4 103/ mm3), 26 (34%) had neutropenia (absolute neutrophil count <1 103/mm3), and 19 (25%) had thrombocytopenia (platelet <150 103/mm3). Image Findings Ultrasound or CT images were unavailable for re-evaluation in 3 patients. Of the 83 patients with images of enlarged lymph nodes, 78 (94%) were ultrasound images and 5 (6%) were CT images. All patients had multiple enlarged lymph nodes, and the most common area of involvement was the posterior triangle at cervical lymph node level V (n = 67, 81%). The mean short and long diameters of the largest lymph node were 9.4 mm (range 3-22 mm) and 19.0 mm (range 10-35 mm), respectively. Also, 39% Kang et al
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ORIGINAL ARTICLES node enlargement (P = .018), and splenomegaly (P = .005) were factors associated with a longer fever duration. As the short diameter of the largest lymph node increased, the fever duration also increased significantly (P = .006). Leukopenia (P < .001), neutropenia (P = .001), elevated erythrocyte sedimentation rate (P = .002), ferritin (P = .006), aspartate aminotransferase (P = .010), and alanine aminotransferase (P = .031) were associated with a longer fever duration (Table III). In a multivariate analysis, high fever peak $39.0 C (P = .010) and presentation with $2 systemic symptoms other than fever (P = .027) were significantly associated with longer fever duration. As the size of the largest lymph node’s short diameter increased, the fever duration increased (P = .015). Leukopenia (P = .022) also had a significant association with a longer fever duration (Table III). Although fever duration did not increase significantly depending on the distribution of the enlarged lymph nodes (P = .242), the presence of fever was significantly associated with conglomerated distribution (P = .002) (Table IV). Patients with conglomerated lymphadenopathy had a longer median duration of fever than those with a separated distribution (11 vs 4.5 days, P = .019), and a higher fever peak ($39 C) (65% vs 27%, P = .001). Also, patients with conglomerated nodes had more systemic symptoms (52% vs 30%, P = .047), as well as abnormal laboratory findings such as leukopenia (89% vs 53%, P = .001) (Table IV).
Table II. Image findings of children diagnosed with KFD No. of cases (%) (N = 83)* Diameter of the largest lymph node Short (mm), mean (SD) Long (mm), mean (SD) Short $10 mm Long $20 mm Bilateral involvement Conglomerated distribution Increased perinodal fat echogenicity
9.4 (3.3) 19.0 (5.5) 32 (39) 36 (43) 21 (26) 45 (54) 70 (84)
*Patients without image findings available for re-evaluation were excluded.
(n = 32) had lymph nodes $10 mm (short diameter) and 43% (n = 36) had lymph nodes $20 mm (long diameter). Increased perinodal fat echogenicity was a characteristic finding, observed in 70 patients’ ultrasound images (84%; Table II). Two distinct types of node distribution were observed: separate (n = 37, 45%) vs conglomerated (n = 46, 54%). Patients with conglomerated nodes had a significantly longer short diameter of the largest lymph node compared with those with separate enlarged lymph node (10.1 mm vs 8.6 mm, P = .043; Table II). Factors Associated with a More Severe Clinical Course Univariate analysis showed that a high fever peak (P < .001), $2 systemic symptoms other than fever (P < .001), bilateral
Table III. Factors associated with longer fever duration in children diagnosed with KFD Univariate analysis
Age at diagnosis Sex Female Male Need for admission Symptoms Fever peak $39.0 C $2 systemic symptoms other than fever Signs (physical findings) Bilateral Lymph node tenderness Hepatomegaly Splenomegaly Rash Diameter of the largest lymph node Short (mm) Long (mm) Laboratory findings* Anemia Leukopenia Neutropenia Thrombocytopenia ESR $30 mm/h CRP $5 mg/dL Ferritin $500 mg/dL LDH $500 mg/dL AST >40 mg/dL ALT >40 mg/dL
Multivariate analysis
Coefficient b
SE
P value
0.215
0.368
.561
1.120 10.022
2.409 2.114
.643 <.001
10.232 8.440
2.084 2.207
<.001 <.001
6.317 0.920 7.873 10.514 5.597
2.622 2.463 7.620 3.598 2.923
.018 .710 .305 .005 .059
0.980 0.156
0.347 0.216
.006 .472
12.129 10.603 8.258 7.577 8.129 2.121 9.884 4.067 6.859 5.916
6.158 2.570 2.457 7.638 2.557 3.291 3.458 5.340 2.573 2.679
.053 <.001 .001 .325 .002 .521 .006 .456 .010 .031
Coefficient b
SE
P value
6.017 5.024
2.279 2.229
.010 .027
5.492
3.269
.097
0.767
0.308
.015
7.885
3.336
.022
4.159
2.763
.139
4.756
2.687
.083
Reference
Definition: anemia (Hb <11 mg/dL); leukopenia (WBC <4.0 103/mm3); neutropenia (ANC <1.0 103/mm3); thrombocytopenia (platelet <150 103/mm3). Patients without radiographic images or fever duration available were excluded: total (N = 81). *Patients whose laboratory findings were unavailable of analysis were excluded: total (N = 73).
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Table IV. Clinical characteristics of patients diagnosed with KFD according to the distribution of the enlarged lymph nodes No. of cases (%) Several separated Conglomerated P (N = 37) (N = 46) value* Symptoms Fever Duration of fever, median d (IQR) Fever $39 C $2 systemic symptoms other than fever Signs (physical findings) Bilateral Lymph node tenderness Hepatomegaly Splenomegaly Rash Oral mucosal ulceration Laboratory findingsz Anemia Leukopenia Neutropenia Thrombocytopenia ESR $30 mm/h CRP $5 mg/dL Ferritin $500 mg/dL LDH $500 mg/dL AST >40 mg/dL ALT >40 mg/dL
22 (59) 4.5 (0-17) 10 (27) 11 (30)
41 (89) 11 (7-18) 30 (65) 24 (52)
.002 .019† .001 .047
6 (16) 20 (54) 1 (3) 3 (8) 6 (16) 1 (3)
15 (33) 32 (70) 1 (2) 6 (13) 10 (22) 4 (9)
.127 .175 1 .725 .586 .375
11 (37) 16 (53) 9 (24) 5 (17) 8 (27) 4 (13) 1 (3) 4 (13) 7 (23) 7 (23)
23 (52) 39 (89) 16 (36) 13 (30) 23 (52) 9 (20) 9 (20) 13 (30) 15 (34) 14 (32)
.237 .001 .624 .273 .033 .541 .042 .159 .438 .6
Definition: anemia (Hb <11 mg/dL); leukopenia (WBC <4.0 103/mm3); neutropenia (ANC <1.0 103/mm3); thrombocytopenia (platelet <150 103/mm3). Patients without radiographic images available for re-evaluation were excluded from the analysis: total (N = 83). *Fisher exact test, Several separated vs conglomerated. †Mann-Whitney U-test, several separated vs conglomerated. zPatients whose lab findings were unavailable of analysis were excluded: total (N = 74); Several separated (N = 30), conglomerated (N = 44).
Treatment and Outcome Two-thirds of the 58 patients were given oral (n = 45) or parenteral (n = 13) antibiotics prior to confirming the diagnosis of KFD, of which oral amoxicillin-clavulanate (36%) was the most commonly prescribed antibiotic. Nonsteroidal anti-inflammatory agents were administered in 44 of the patients (51%) for managing systemic symptoms after the diagnosis of KFD was confirmed. Although a majority of the patients’ symptoms improved with conservative management, oral prednisolone was administered in 24 of the patients (28%), and of these, 16 (67%) had a prolonged fever lasting $2 weeks prior to steroid administration (P = .001). The following dosages of oral prednisolone were administered: 1.5 mg/kg/d in 4%, 1 mg/kg/d in 67%, 0.5 mg/kg/ d in 29% of patients. The duration of corticosteroid treatment was #7 days in 63% of the patients, whereas 38% were administered corticosteroids for 8-12 days. Of 19 patients with the time to defervescence after initiating corticosteroid treatment recorded, 15 (79%) had defervescence within 24 hours, 3 (16%) within 48 hours, and only 1 patient required up to 72 hours. Although several factors were considered when initiating corticosteroid treatment, prolonged fever after histopatho4
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logic confirmation (n = 17; 71%) was the most common. Other reasons included large neck mass (n = 9), aggravating pancytopenia (n = 8), extreme fatigue (n = 1), and recurrence (n = 1). Overall, recurrence occurred in 10% (n = 9) of the patients. The duration of fever was not associated with recurrence (only 2 of 9 had prolonged fever), and a male predominance was observed (n = 8; 88%).
Discussion KFD has a wide clinical spectrum and although generally is self-limiting, some patients suffer more than others from prolonged systemic symptoms during the course of the disease.4,5,10 In this study, we found that KFD occurred mostly in the early adolescence, and as previously reported in other studies on children, cervical lymph node enlargement and fever were predominating symptoms.8,9 Most, but not all, patients had cervical lymph node involvement, and similar to other studies, the absence of fever did not exclude KFD.5 Patients included in this study had shorter lengths of illnesses compared with other studies,6 with a median of 9 days of fever. A possible reason for this difference is that KFD encompasses a wide spectrum of disease severity, and patients from mild to severe clinical spectrums were included. Enlarged lymph nodes in the posterior triangle at cervical lymph node level V were most commonly involved and lymph node tenderness was observed in more than two-thirds of patients. Although KFD is known to be a self-limiting disease, symptoms can persist over weeks as shown in our study. During the prolonged course of illness, children suffer from decreased school performance, numerous visits to clinics, admissions to the hospital, and/or acute deterioration of health. Many studies have reported the dramatic effects of corticosteroids, which are administered as immune modulators in patients that suffer from prolonged fever.13-15 In this study, patients with a higher fever peak that reached above 39 C, and those who had more systemic symptoms such as loss of appetite, fatigue, and headache had significantly longer fever duration. The short diameter of the largest lymph node, as well as leukopenia, which was previously reported to be significantly associated with prolonged fever in KFD,9 were significantly associated with longer fever duration in our study. Considering the self-limiting nature of the disease and the potential adverse effects of corticosteroids, treatment should be considered in selected cases, potentially using factors we identified as significantly associated with a more severe and protracted clinical course. There are numerous causes of cervical lymphadenopathy, and understanding the characteristic sonographic findings of KFD aids in the differential diagnosis. In KFD, nodes typically show focal low attenuation and perinodal infiltration.20 A study on 175 adults with KFD suggested that perinodal echogenicity is a characteristic finding in KFD.21 Likewise, in this study, a majority of the patients had perinodal fat echogenicity. Kang et al
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ORIGINAL ARTICLES
We characterized 2 distinct distribution types of the enlarged nodes, conglomerated and separate. In our study, patients with conglomerated distribution had a significantly more severe disease course, with longer fever duration, higher fever peak, and more systemic accompanying symptoms. Leukopenia as well as elevated erythrocyte sedimentation rate and ferritin level also was more common in these patients. A major limitation to this study was its retrospective nature, and the possibility of incomplete medical records. However, all patients included in this study had recordings of their physical findings and clinical symptoms, and only patients with fever peaks and duration recorded in the electronic medical records were included in the analysis on fever duration and lymph node distribution. Another limitation was that the patients were all from a single center. However, because it was a single center study, there was an advantage that the physicians, radiologists, and surgeons involved in treating the cases were relatively uniform in assessments and management, thus reducing biases. KD, in general, is a self-limiting disease; however, some patients have a more severe and prolonged course. Patients with high fever, more systemic symptoms, leukopenia, and larger lymph nodes with a conglomerated distribution may benefit from early recognition so that benefits and risks of corticosteroid therapy can be selectively weighed. n Submitted for publication Aug 21, 2015; last revision received Oct 27, 2015; accepted Dec 23, 2015. Reprint requests: Hyunju Lee, MD, Department of Pediatrics, Seoul National University Bundang Hospital, 82, Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, Republic of Korea 463-707. E-mail: mdopd@ hanmail.net or [email protected]
References 1. Kim YM, Lee YJ, Nam SO, Park SE, Kim JY, Lee EY. Hemophagocytic syndrome associated with Kikuchi’s disease. J Korean Med Sci 2003; 18:592-4. 2. Chen JS, Chang KC, Cheng CN, Tsai WH, Su IJ. Childhood hemophagocytic syndrome associated with Kikuchi’s disease. Haematologica 2000;85:998-1000. 3. Lin YW, Horiuchi H, Ueda I, Nambu M. Recurrent hemophagocytic lymphohistiocytosis accompanied by Kikuchi’s disease. Leuk Lymphoma 2007;48:2447-51.
4. Dorfman RF, Berry GJ. Kikuchi’s histiocytic necrotizing lymphadenitis: an analysis of 108 cases with emphasis on differential diagnosis. Semin Diagn Pathol 1988;5:329-45. 5. Kucukardali Y, Solmazgul E, Kunter E, Oncul O, Yildirim S, Kaplan M. Kikuchi-Fujimoto disease: analysis of 244 cases. Clin Rheumatol 2007; 26:50-4. 6. Feder HM Jr, Liu J, Rezuke WN. Kikuchi disease in Connecticut. J Pediatr 2014;164:196-200.e1. 7. Sunghoon C, Park S, Lee K, Song J, Han M, Choi Y, et al. Clinical characteristics of Kikuchi disease in children. Pediatr Infect Vaccine 2007;14: 129-35. 8. Seo JH, Shim HS, Park JJ, Jeon SY, Kim JP, Ahn SK, et al. A clinical study of histiocytic necrotizing lymphadenitis (Kikuchi’s disease) in children. Int J Pediatr Otorhinolaryngol 2008;72:1637-42. 9. Chuang CH, Yan DC, Chiu CH, Huang YC, Lin PY, Chen CJ, et al. Clinical and laboratory manifestations of Kikuchi’s disease in children and differences between patients with and without prolonged fever. Pediatr Infect Dis J 2005;24:551-4. 10. Lee KY, Yeon YH, Lee BC. Kikuchi-Fujimoto disease with prolonged fever in children. Pediatrics 2004;114:e752-6. 11. Lin HC, Su CY, Huang SC. Kikuchi’s disease in Asian children. Pediatrics 2005;115:e92-6. 12. Tsang WY, Chan JK. Fine-needle aspiration cytologic diagnosis of Kikuchi’s lymphadenitis. A report of 27 cases. Am J Clin Pathol 1994;102:4548. 13. Yoshioka K, Miyashita T, Nakamura T, Inoue T, Yamagami K. Treatment of histiocytic necrotizing lymphadenitis (Kikuchi’s disease) with prolonged fever by a single course of methylprednisolone pulse therapy without maintenance therapy: experience with 13 cases. Intern Med 2010;49:2267-70. 14. Jang YJ, Park KH, Seok HJ. Management of Kikuchi’s disease using glucocorticoid. J Laryngol Otol 2000;114:709-11. 15. Yalcin S, Toprak SK, Erismis B, Altundag O, Ozdemir H, Topcuoglu N. Management of Kikuchi-Fujimoto disease using glucocorticoid: a case report. Case Rep Med 2011;2011:230840. 16. Fujimoto Y, Kojima Y, Yamaguchi K. Cervical subacute necrotizing lymphadenitis. Naika 1972;30:920-7. 17. Feller AC, Lennert K, Stein H, Bruhn HD, Wuthe HH. Immunohistology and aetiology of histiocytic necrotizing lymphadenitis. Report of three instructive cases. Histopathology 1983;7:825-39. 18. Facchetti F, de Wolf-Peeters C, Van Den Oord JJ, De Vos R, Desmet VJ. Plasmacytoid monocytes (so-called plasmacytoid T-cells) in Kikuchi’s lymphadenitis. An immunohistologic study. Am J Clin Pathol 1989;92: 42-50. 19. Bosch X, Guilabert A, Miquel R, Campo E. Enigmatic Kikuchi-Fujimoto disease a comprehensive review. Am J Clin Pathol 2004;122:141-52. 20. Kwon SY, Kim TK, Kim YS, Lee KY, Lee NJ, Seol HY. CT findings in Kikuchi disease: analysis of 96 cases. AJNR Am J Neuroradiol 2004;25: 1099-102. 21. Yoo JL, Suh SI, Lee YH, Seo HS, Kim KM, Shin BK, et al. Gray scale and power Doppler study of biopsy-proven Kikuchi disease. J Ultrasound Med 2011;30:957-63.
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12 10 8 6 4 2 0 5
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11 12 13 Age (years)
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Figure 1. Age distribution of the patients diagnosed with KFD.
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No. of patients
30 25 20 15 10 5 0 Spring
Summer Fall Season
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Figure 2. Seasonal distribution of the patients diagnosed with KFD (Spring: March, April, May; Summer: June, July, August; Fall: September, October, November; Winter: December, January, February). 5.e1
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