ORIGINAL ARTICLE

Characteristics of Kikuchi–Fujimoto diseasein children compared with adults

Tae Yeun Kim & Kee-Soo Ha & Yunkyung Kim &

JungHwa Lee & KwangChul Lee & JooWon Lee

Received: 19 July 2013 /Accepted: 30 July 2013 /Published online: 17 August 2013# Springer-Verlag Berlin Heidelberg 2013

Abstract Kikuchi–Fujimoto disease (KFD) is a benign, self-limiting disease characterized by cervical lymphadenopathy.Although it was primarily thought to be a disease of youngadults, it has been increasingly recognized in children. Todefine the characteristics of KFD in children, we reviewedthe medical records of patients younger than 18 years of agewho were diagnosed with KFD from 2001 to 2012 at KoreaUniversity Medical Center, as well as worldwide publishedreports of KFD. A total of 140 pediatric patients and 733patients of all ages was analyzed. Compared to the femalepredominance found in adults (2:1), young boys were morecommonly affected than young girls (1.4:1). Cervical lymph-adenopathy was the most common clinical finding in children,as it was in adults. Lymphadenopathy was more likely to betender (69 vs. 44 %, p<0.001) but less generalized (1 vs. 8 %,p<0.05) in children compared to adults. Fever (82 vs. 35 %,p<0.001) and rash (10 vs. 4 %, p<0.05) were observed inchildren more commonly than in adults. Leukopenia wasobserved in 50 and 38 % of children and adults, respectively.Rates of recurrence and association with autoimmune

diseases in children were comparable to those of adults.Cervical lymphadenopathy was the most common clinicalmanifestation of KFD in all ages. While fever and rash weremore common in children with KFD compared to adults,generalized lymphadenopathy was rarer.

Keywords Kikuchi–Fujimoto disease . Lymphadenopathy .

Fever . Children

Introduction

Kikuchi–Fujimoto disease (KFD), also known as histiocyticnecrotizing lymphadenitis, is a benign and self-limiting dis-ease frequently affecting Asian females younger than 30 yearsof age. It was first reported independently by Kikuchi [12] andFujimoto et al. [9] in 1972. The cause of KFD is not known,but it is commonly manifested as cervical lymphadenopathy,fever, and leukopenia. Infectious agents including Yersinia,Toxoplasma, Epstein–Barr virus, human herpes virus 6 and 8,human T-lymphotropic virus type 1, and parvovirus B19 havebeen reported to have a causative role, but this has not beenconfirmed [1]. The female predominance and histopathologicsimilarity with lupus lymphadenitis suggest a possible associ-ation in pathogenesis between KFD and systemic lupuserythematosus (SLE) [8, 11, 20]. Since there are no laboratoryfindings consistent with KFD, the diagnosis of KFD is basedon the characteristic histopathologic findings of affectedlymph nodes. Most patients eventually recover from KFDwithout specific treatment, but the later development of auto-immune diseases has been reported [4, 15, 22, 29].

Although it was primarily thought to be a disease of youngadults, KFD has been increasingly recognized in Asian chil-dren [5, 19, 20, 23, 27]. The increase in attention to this diseasemay have contributed to the recent increase in pediatric reportsof KFD, and therefore its true incidence in children may be notas rare as previously thought. Cervical lymphadenopathy is a

T. Y. Kim :Y. Kim : J. Lee :K. Lee : J. LeeKorea University School of Medicine, 73 Inchon-ro, Sungbuk-gu,Seoul 136-705, Republic of Korea

K.<S. Ha : J. Lee (*) : J. LeeDepartment of Pediatrics, Korea University Medical Center GuroHospital, 148 Gurodong-ro, Guro-gu, Seoul 152-703,Republic of Koreae-mail: leejmd@chol.com

Y. KimDepartment of Pediatrics, Korea University Medical Center AnsanHospital, Kojan-dong, Ansan-si, Kyunggi-do 425-707,Republic of Korea

K. LeeDepartment of Pediatrics, Korea University Medical Center AnamHospital, Anam-dong, Sungbuk-gu, Seoul 136-705,Republic of Korea

Eur J Pediatr (2014) 173:111–116DOI 10.1007/s00431-013-2131-3

condition that ranges in severity from very benign to verymalignant and is frequently encountered in various diseasesin children. Since the histopathologic findings of the affectednodes are not pathognomonic, biopsy cannot always provide astraightforward diagnosis [1–3, 21, 30]. Considering theimmunopathogenic nature of KFD, the clinical manifestationsof KFD in children might be different compared with those inadults. In order to correctly diagnose and avoid unnecessaryexaminations and treatments, we attempted to accurately de-fine pediatric KFD.

Materials and methods

We reviewed the medical records of 40 KFD patients youngerthan 18 years of age who were treated at Korea UniversityMedical Center from January 2001 to January 2012. Thisstudy was approved by the Institutional Review Board ofKorea University Medical Center. The diagnosis of KFDwas made on the basis of histopathologic findings of affectedlymph nodes obtained by fine needle aspiration (FNA) orexcisional biopsy after exclusion of other diseases, i.e., mul-tifocal necrosis in the paracortical area with karyorrhecticdebris and various histiocytes with crescentic nuclei in theabsence of neutrophils [1, 11, 30]. Initially, FNA wasperformed in 35 patients and excisional biopsy in 5 patients.FNA cytology was diagnostic in 31 of 35 patients, and theremaining 4 patients needed additional excisional biopsy. Thedecision on the performance and timing of the histocytologicconfirmation was made depending on the patient's conditionand the severity and duration of manifestations before andafter admission to our center. We searched worldwide forEnglish language reports of KFD involving more than 70patients without a restriction on age and more than 30 patientswith a restriction on age of 18 or under. Clinical features,laboratory findings, courses, and follow-up results were col-lected and analyzed. Follow-up at our center was available for23 patients at least 9 months after recovery. Statistical analysiswas performed using SPSS 20. The data were expressed asmean ± standard deviation or percentage where appropriate.The differences between data were analyzed by the χ2 test. Ap value <0.05 was considered to be statistically significant.

Results

Summary of initial manifestations of pediatric KFD in ourcenter

Over an 11-year period, a total of 40 patients was diagnosedwith KFD (23 boys and 17 girls; ratio of boys/girls, 1.4:1).Their ages ranged from two to 18 years with a mean age of11 years. The sex ratio differed according to age range; the

ratio of boys/girls was 2:1 for ages 2–5 years, 1.7:1 for ages 6–10 years, 1.4:1 for ages 11–14 years, and 1:3 for ages 15–18 years. Although a seasonal predominance was not evident,occurrence was more common during winter and summer. Allpatients presented with lymphadenopathy, with cervical nodesinvolved in 36 patients (90 %). Affected nodes were com-monly tender (82 %), multiple (83 %), unilateral (69 %), andless than 3 cm in diameter (65 %). Paravertebral and ilealmesenteric lymphadenopathies without cervical lymphade-nopathy were each noted in one patient. No patients demon-strated generalized lymphadenopathy involving two or moreanatomic sites. Thirty-six patients (90%) had fever (>37.5 °C)with a mean duration of 17.4 days. Atypical rash was ob-served in five patients (13 %) and hepato- and splenomegalyin one and two patients, respectively. Leukopenia (<4,000/μL)was noted in 18 patients (45 %), and leukocytosis (>10,000/μL) was found in four patients (10 %). Six patients (15 %)presented with thrombocytopenia (<150,000/μL). Inflamma-tory indices such as erythrocyte sedimentation rate and C-reactive protein were elevated in 29 (73 %) and 24 patients(60 %), respectively. Regarding liver function tests, aspartateaminotransferase was elevated in 11 patients (28 %) andalanine aminotransferase was elevated in nine patients(23 %). Lactate dehydrogenase was measured in 33 patients,and 29 (88 %) were found to have a level greater than 500 U/L. Anti-nuclear antibody (ANA) was measured in 18 patients,and 5 (28 %) were positive, ranging from 1:40 to 1:80.Patients were initially administered antibiotics or non-steroidal anti-inflammatory drugs, and if fever and/or lymph-adenopathy persisted, they were given oral steroids, which ledto resolution within 1–3 days. All patients eventually recov-ered without sequelae. Among 23 patients who were followedup for longer than 9 months (mean 3.47±2.4 years), recurrentKFD was evident on re-biopsy 9 months later in 1 patient.Additionally, Sjogren's syndrome developed 3.5 years later inone patient; his initial ANA when KFD was diagnosed wasweakly positive (1:40). Data are summarized in Table 1.

Characterization of pediatric KFD with fever in our center

In this analysis, we also attempted to characterize feveraccording to blood leukocyte count. To clarify differences,comparisons were made between patients with leukopeniaand patients with leukocytosis. All four patients with leukocy-tosis and 17 of 18 patients with leukopenia had fever. Althoughit is difficult to calculate significances in groups with only fourpatients, while patients with leukocytosis were all young boys(8±5.0 vs. 11.4±2.2 years), leukopenic patients demonstrated asimilar sex ratio but fewer platelets (185±51 vs. 270±33×103/μL) and longer durations of fever (18.9±7.5 vs. 10.8±4.3 days).Blood leukocyte count had a tendency to be inversely correlat-ed with fever duration in all 36 febrile patients, especially in therange of leukocytosis.

112 Eur J Pediatr (2014) 173:111–116

Tab

le1

Manifestatio

nsof

Kikuchi–F

ujim

otodiseasein

child

rencomparedwith

adults

Features

Childrenonly

Allages

Chuangetal.[5]

Zou

etal.[33]

Kim

etal.(presentreport)

Meanof

theseries

Dorfm

anetal.[7]

Kikuchietal.[13]

Tsangetal.[30]

Kuo.etal.[16]

Cheng

etal.[4]

Meanof

theseries

Num

berof

patients

6436

40108

276

7579

195

Country

Taiwan

China

Korea

USA

Japan

HongKong

Taiwan

Taiwan

Publishedyear

2005

2009

2013

1988

1990

1994

1995

2010

Sexratio

(F/M

)29:35

13:23

17:23

59:81(1:1.4)

85:23

168:109

55:20

41:38

141:54

490/244(2:1)**

Age

(year)

Range

2–18

1.5–13.9

2–17

1.5–18

11–75

4–53

9–57

9–54

6–55

4–75

Mean

10.1

1130

26.9

25.5

26.9

24.6

Median

1626

Lymphadenopathy

(%)

Cervicaln

odes

63/64(98)

33/36(92)

36/40(90)

132/140(94)

86/108

(79)

269/276(98)

68/75(91)

77/79(98)

191/195(98)

691/733(94)

Tenderness

32/64(50)

32/36(89)

31/38(82)

95/138

(69)

13/92(14)

42/71(59)

104/195(53)

159/358(44)**

Unilaterality

52/63(83)

25/36(69)

77/99(78)

146/191(76)

146/191(76)

Peritoneal/retroperitoneallymphadenopathy

(%)

6/21

(29)

1/40

(3)

7/61

(11)

2/75

(3)

Generalized

lymphadenopathy

(%)

1/64

(2)

0/40

(0)

1/104(1)

6/108(6)

31/276

(11)

4/75

(5)

1/79

(1)

42/538

(8)*

Fever(%

)21/64(33)

a26/36(72)

36/40(90)

62/76(82)

36/108

(33)

83/276

(30)

20/52(39)

30/62(48)

74/195

(38)

243/693(35)**

Hepatom

egaly(%

)5/64

(8)

4/36

(11)

1/40

(3)

10/140

(7)

2/108(2)

2/108(2)

Splenomegaly(%

)2/40

(5)

2/40

(5)

7/108(6)

7/108(6)

Rash(%

)4/64

(6)

5/36

(14)

5/40

(13)

14/140

(10)

4/108(4)

8/195(4)

12/303

(4)*

Lab

(%)

Leukopenia

26/59(44)

24/36(67)

18/40(45)

68/135

(50)

8/40

(20)

84/144

(58)

15/33(46)

30/70(43)

28/148

(19)

165/435(38)*

Leukocytosis

2/59

(3)

4/40

(10)

6/99

(6)

3/144(2)

2/70

(3)

2/148(1)

7/362(2)

Anemia

2/58

(3)

6/36

(28)

11/40(28)

19/134

(14)

Throm

bocytopenia

5/54

(9)

4/36

(11)

6/40

(15)

15/130

(12)

8/148(5)

8/148(5)

IncreasedESR

5/12

(42)

31/36(86)

29/40(73)

65/88(74)

15/19(79)

15/19(79)

IncreasedCRP

5/19

(26)

5/36

(14)

24/40(60)

34/95(36)

18/47(38)

18/47(38)

HighLDH

29/33(88)

29/33(88)

42/80(53)

42/80(53)**

ANA(+)

3/19

(16)(≥1:80)

1/15

(7)

5/18

(28)

(≤1:80)

9/52

(17)

1/16

(6)

4/45

(9)(≥1

:320)

5/61

(8)

Follow-up,months(m

edian(range))

22.5(2–192)

42(9–128)

32(1–120)

(6–60)

23(2–84)

52(6–204)

Recurrence(%

)2/46

(4)

1/23

(4)

3/69

(4)

3/64

(5)

11/276

(4)

1/32

(3)

2/59

(3)

14/96(15)

b17/431

(4)

Associatedautoim

muneds

(%)

2/46

(4)

1/23

(4)

3/69

(4)

2/64

(2)

4/55

(7)

5/96

(5)

11/215

(5)

ESR

erythrocytesedimentatio

nrate,C

RPC-reactiveprotein,LDHlactatedehydrogenase,ANAanti-nuclearantib

ody

*p<0.05

(resultsstatistically

differentfrom

meanof

pediatricKikuchi–F

ujim

otodisease);*

*p<0.001(resultsstatistically

differentfrom

meanof

pediatricKikuchi–F

ujim

otodisease

aPercentage

ofpatientswhose

body

temperature

>38

°Cthatlasted

for>1week

bClin

icalrecurrence

Eur J Pediatr (2014) 173:111–116 113

Comparison of manifestations of KFD between childrenand adults [4, 5, 7, 13, 16, 30, 33]

A literature search for KFD studies identified the two pediatricstudies and five adult studies presented in Table 1. Althoughthe adult studies also included children, the mean ages in thosestudies were older and were therefore considered to representadult KFD. While the overall sex ratio of the adult studiesshowed a twofold female predominance, the pediatric studiesshowed a male predominance (1.4:1) (p<0.001). Cervicallymphadenopathy was observed in more than 90% of patientsin all studies except for one study performed in the USA.Compared with adults, children more often presented withtender lymphadenopathy (69 vs. 44%, p<0.001). Generalizedlymphadenopathy was rarely observed in children. In thecomparison of fever, a study by Chuang et al. [5] was exclud-ed because it included patients with prolonged high fever.Consequently, fever was far more prevalent in children thanadults (82 vs. 35 %, p<0.001). Although rash was not com-mon, it was observed more often in children than in adults (10vs. 4 %, p<0.05). While leukopenia was frequently observedin both, it was more common in children (50 vs.38 %,p<0.05). Increased erythrocyte sedimentation rate, rather thanincreased C-reactive protein, was frequently observed in bothadults and children. High ANA (≥1:320) was rare in childrencompared with adults. Biopsy-proven recurrence was about4 % in both adults and children, whereas clinical recurrencewas 15 % in a Taiwanese study of adults. The development ofautoimmune diseases was similarly associated in children andadults.

Discussion

In accordance with the increasing recognition of KFD inchildren, a definition of the manifestations of KFD in childrenas compared with adults is needed. Despite the immuno-pathogenic mechanism of KFD, the immaturity of the immunesystems of children may not play a role in pathogenesis, sinceKFD is a disease of young adults rather than young children[15, 28]. Whereas most adult studies have shown a femalepredominance, most pediatric studies have reported a malepredominance [5, 10, 19, 20, 26, 31]. Our study also revealedmore boys and an overall female to male sex ratio of 1:1.4, butwhenwe analyzed this ratio according to age range, the data ofour center showed a predominance of boys in the range of14 years of age or under (1:1.6) and a predominance of girls inthe range of 15 years of age or over (3:1). Among five studiesof patients of all ages, presented in Table 1, a US studyshowed the highest mean age of patients as well as the highestfemale predominance (4:1). It is possible that the overall sexratio of KFD is affected by the age distribution of the patientsincluded in each study. Since most girls in Korea enter puberty

around the age of 15 years, it is possible that female sexhormones play a role in the pathogenesis of KFD, similar toSLE, but this requires further investigation.

Unilateral cervical lymph nodes are most commonly af-fected in KFD. The affected nodes in our pediatric KFDpatients were commonly tender, multiple, unilateral, and lessthan 3 cm in diameter. Compared with adults, children werepreviously reported to have significantly more tender lymph-adenopathy and less unilaterality [26]. The involvements ofsmall and multiple lymph nodes have been reported to becommon findings of KFD rather than lymphoma [17]. Where-as cervical nodes are most commonly affected, internal nodesare infrequently involved. Generalized lymphadenopathy wasobserved in 8 % of adults but was rarely seen in children. Incontrast, 82 and 10 % of children had fever and rash, respec-tively, compared with about 35 and 4% of adults, representingmore systemic symptoms in children than adults. Leukopeniais a very consistent finding in KFD [1, 5, 10, 13, 16, 17, 19,23, 25–28, 30, 31]. Children with KFD who present withprolonged high fever have been reported more frequently tobe leukopenic [5]. While this was also observed in our center,the opposite is not necessarily true. Our data showed thatduration of fever in leukopenic children was variable, whereasit was relatively shorter in children with leukocytosis. Thelonger duration of fever in leukopenic children in general inour center was not due to delayed intervention, since theirpost-admission fever was also prolonged. Compared withchildren with leukocytosis, leukopenic children were olderand also showed lower platelet counts. Although suppressedgranulopoiesis has been suggested as a mechanism for leuko-penia in KFD [6], the relationship between fever and leuko-penia has not been evaluated in adult studies. Whether thedifference in manifestations of KFD between children andadults reflects an intrinsic difference in immune maturationrequires further investigation.

Manifestations of KFD have been reported differentlyaccording to country; for example, Israeli and German studiespresented more systemic findings compared with other coun-tries [24, 25]. This may be due in part to genetic variabilityamong different ethnic groups or because KFD may begrouped with other several disease entities with similar histo-pathologic findings [25]. relationship between the clinicalfeatures and histologic types of KFD has been suggested, butthis remains controversial [16, 25]. Since most pediatric cases ofKFD are reported from Far East Asia [5, 10, 19, 20, 23, 26, 27,31, 33], we could not evaluate ethnic differences affecting themanifestations.

An infectious etiology, in particular viral, has been sug-gested in the pathogenesis of KFD, but this has not beenconfirmed. Immunization has also been reported as a potentialtrigger associated with the development of KFD [32]. It ispossible that an immune response triggered by infectiousagents is exaggerated in KFD [1, 7, 11]. While the absence

114 Eur J Pediatr (2014) 173:111–116

of circulating autoantibodies does not support an autoimmunemechanism in KFD, abundant karyorrhectic debris in affectednodes in KFD has the potential to increase the chance to spillautoantigens, stimulating the production of autoantibodies andthe eventual development of autoimmune diseases, especiallyin genetically susceptible individuals [6, 11, 22]. Often, thehistopathologic findings of affected lymph nodes cannot dif-ferentiate KFD from lupus [7, 14, 16]. This might represent acontinuum provoked by a common inciting event, althoughKFD is self-limited, whereas lupus proceeds for a longerduration [8, 20]. ANA is detected much more commonly incases from East Asia and Far East Asia than in European cases(23 vs. 3 %, p=0.00017), and an SLE association is morecommon as well (28 vs. 9 %, p=0.000214) [15]. One quarterof our pediatric cases showed weakly reactive ANA in con-trast with a study performed in adults by Cheng et al. thatshowed highly reactive ANA in 9 % of patients. The devel-opment of autoimmune diseases in children and adults wassimilarly associated in 4 % of patients. Although theinitial statuses of ANA in patients with later autoim-mune diseases in the study by Cheng et al. were notidentified, ANA positivity, rather than titer, might beimportant in terms of the development of autoimmunediseases. Although only one case of Sjogren's syndromewas identified in our center, SLE has been reported asthe most common autoimmune disease associated withKFD [15].

KFD recurs more frequently than previously thought, con-sidering that not all recurred KFDs are re-biopsied. While thebiopsy-proven recurrence of KFD was around 4 % in moststudies, clinical recurrencewas 15% in the study performed inadults by Cheng et al. Recurrent KFDwas reported to be morelikely to have extranodal involvement, longer duration ofsymptoms, and positive ANA [28].

KFD is more prevalent in Asia compared with the Westernworld. In the past, when KFD was rarely recognized in chil-dren, the benign nature of KFD was emphasized, and unnec-essary examinations and treatments were avoided. However,more pediatric patients are now being recognized, and societyis becomingmore familiar with KFD. At this time, it should bekept in mind that KFD is a disease of exclusion, since even thehistopathologic findings of affected lymph nodes, which arethe only diagnostic method for KFD, are not pathognomonic.In children in particular, fever and lymphadenopathy are com-mon manifestations of many serious life-threatening condi-tions. Malignant lymphoma, incomplete Kawasaki disease,and hemophagocytic lymphohisiocytosis can manifest inways that are indistinguishable fromKFD [18, 21]. In additionto the histologic differentiation of lymphadenopathies fromvarious diseases, recognition of common initial features ofpediatric KFD might help to differentiate the diagnosis. Com-plete work-ups before and long-term follow-ups after thediagnosis of KFD are necessary.

This study has some limitations. First, the number of pedi-atric patients in the study was small compared with adultstudies. Second, manifestations were not clearly defined instudies, and therefore, for example, fever and rash could onlybe compared as to whether or not they were accompanied.Third, since not all laboratory data were available for childrenand adults, we could not compare laboratory differences thatmight explain the differences in manifestations between chil-dren and adults. Additionally, ANA was measured in only asmall number of patients, and therefore the relationship be-tween ANA and the association of autoimmune diseasesshould be interpreted cautiously. Fourth, only a limited num-ber of patients in included studies were closely followed, andtherefore the incidence of associated autoimmune diseasemight not be representative. Despite these limitations, thisstudy suggests some significant differences in the manifesta-tions of KFD between children and adults, including moresystemic manifestations such as fever and rash in children.

In conclusion, it is very likely that KFD is a sequentialhistopathologic manifestation of lymph nodes resulting fromvarious initiating events, possibly including viral infections. Inaddition to tender cervical lymphadenopathy, pediatric KFDincorporates more systemic manifestations such as fever andrash. Since even the histopathologic findings of KFD are notpathognomonic, the complete exclusion of other serious dis-eases that share common clinical manifestations is essential inchildren. Although most cases of KFD take very benignclinical courses, long-term follow-up is necessary to monitorfor the possible later development of autoimmune disease.

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