Kyung-Yil Lee, Yeong-Heum Yeon and Byung-Churl Lee 2004;114;e752

Kikuchi-Fujimoto Disease With Prolonged Fever in Children
Kyung-Yil Lee, Yeong-Heum Yeon and Byung-Churl Lee
Pediatrics 2004;114;e752; originally published online November 15, 2004;
DOI: 10.1542/peds.2004-0485
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Kikuchi-Fujimoto Disease With Prolonged Fever in Children
Kyung-Yil Lee, MD; Yeong-Heum Yeon, MD; and Byung-Churl Lee, MD
ABSTRACT. We reviewed 12 patients who had Kikuchi-Fujimoto disease (KFD) and presented with prolonged fever and lymphadenopathy. The clinical and
laboratory aspects of the patients confirmed by excisional lymph node biopsy were analyzed. The mean age
of the children was 11.0 ⴞ 3.0 years (range: 6 –15 years).
The male-to-female ratio was 1.4:1. The median duration
of fever before admission and the total duration of fever
was 13 days (range: 7– 65 days) and 19.5 days (range: 9 –75
days), respectively. One patient had supraclavicular
lymphadenopathy, 10 had cervical involvement, and 1
had axillary lymphadenopathy. All of the histologic findings of the lymph node biopsies showed the characteristic findings consistent with KFD, such as paracortical
necrosis with karyorrhexis and an increase in the number
of phagocytic histiocytes and atypical lymphocytes. As
for the laboratory findings, leukopenia (3600 ⴞ 900 per
mm3), anemia (hemoglobin 11.4 ⴞ 1.2 g/dL), an elevated
erythrocyte sedimentation rate (44 ⴞ 18 mm/hour), and a
relatively low C-reactive protein level (1.3 ⴞ 1.1 mg/dL)
were noted. Eight patients received conservative therapy
with antipyretics, and 3 patients were treated with prednisolone. KFD is a rare disease yet should be considered
in the differential diagnosis for older children with prolonged fever and lymphadenopathy. Pediatrics 2004;
114:e752–e756. URL: www.pediatrics.org/cgi/doi/10.1542/
peds.2004-0485; Kikuchi-Fujimoto disease, subacute necrotizing lymphadenitis, prednisolone.
ABBREVIATIONS. KFD, Kikuchi-Fujimoto disease; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; LDH, lactate
dehydrogenase.
K
ikuchi-Fujimoto disease (KFD) is a self-limiting disease that has an unknown cause and
was first described independently in 1972 by
Kikuchi1 and Fujimoto et al2 in Japan. This disease
has now been recognized in many other countries
and has also been referred to as Kikuchi’s disease,
histiocytic necrotizing lymphadenitis, focal histiocytic lymphadenitis, and subacute necrotizing
lymphadenitis.3–10
The characteristic clinical presentation of the disorder includes cervical lymphadenopathy and prolonged fever. Its natural course is usually benign,
From the Department of Pediatrics, Catholic University of Korea, College of
Medicine, Seoul, Republic of Korea.
Accepted for publication Jul 1, 2004.
doi:10.1542/peds.2004-0485
No conflict of interest declared.
Reprint requests to (K.-Y.L.) Department of Pediatrics, Catholic University
of Korea, Daejeon St Mary’s Hospital, 520-2 Daeheung-dong, Jung-gu,
Daejeon 301-723, Republic of Korea. E-mail: [email protected]
PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Academy of Pediatrics.
e752
and the clinical symptoms and signs disappear
within a few months without specific treatment. Because the clinical findings and laboratory examinations are nonspecific, the correct diagnosis requires a
histopathologic examination by lymph node biopsy.
If the clinician is unaware of the disorder or if the
lymphadenopathy is not prominent at presentation,
then delayed diagnosis and unnecessary investigations for a “fever of unknown origin” can occur. KFD
affects individuals of all ages, particularly young
women, but there are just a few descriptions of this
disease in the pediatric literature.11–16 In this study,
we evaluated the clinical and laboratory characteristics of 12 patients with KFD confirmed by lymph
node biopsy.
METHODS
We retrospectively analyzed the medical charts of 12 patients
who had KFD and presented with a prolonged fever of ⬎10 days.
Seven patients were admitted to Catholic University of Korea,
Daejeon St Mary’s Hospital (patients 1–7), and 5 patients were
admitted to St Mary’s Hospital (patients 8 –12) from 1996 through
2003. All patients’ disease was diagnosed histologically by an
excision lymph node biopsy. All histologic findings from the
biopsies were consistent with a diagnosis of KFD, manifesting as
a paracortical patchy eosinophilic fibrinoid necrosis with karyorrhexis and an increase of lymphohistiocytic infiltrates. These infiltrates included mononuclear cells, histiocytes, and atypical lymphocytes (Figs 1 and 2, obtained from patient 2). The clinical
characteristics, status of affected lymph nodes, associated symptoms, and laboratory findings from the medical records are presented.
RESULTS
Clinical Characteristics
The mean age of the patients was 11.0 ⫾ 3.0 years,
ranging from 6 to 15 years. The male-to-female ratio
was 1.4:1. The median fever duration before hospital
admission was 13 days (range: 7– 65 days), and the
median total duration of the fever was 19.5 days
(range: 10 –75 days). Lymphadenopathy (lymph
node size ⱖ1 cm and showing tenderness) was noted
at the cervical regions in 10 patients, in the axillary
region in 1 patient, and in the supraclavicular region
in 1 patient. In this series, the mean size of affected
lymph nodes on biopsy was 1.5 ⫻ 2.0 cm. All patients experienced tenderness of the affected lymph
node, regardless of the node’s size, during the febrile
period. As for other extranodal manifestations, 1 patient (patient 2) had a transient skin rash on the trunk
that was of a maculopapular nature, and 1 patient
presented with weight loss and night sweats (patient
7; Table 1). All patients except 1 (patient 12) became
afebrile within 2 days after lymph node biopsy. In 4
patients (patients 3, 4, 7, and 10), the fever subsided
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Fig 1. Ill-defined necrotic area containing karyorrhexis surrounded by lymphohistiocytic infiltration in the paracortex.
Magnification: ⫻40 (hematoxylin and
eosin).
Fig 2. Plasmatoid monocytes infiltration with large amount of karyorrhexis
in the necrotic area. Magnification:
⫻400 (hematoxylin and eosin).
before lymph node biopsy. Two patients (patients 1
and 2) showed recurrent fever 3 to 4 days after
lymph node excision; this fever lasted several days
and quickly responded to prednisolone treatment (1
mg/kg for 5–7 days, and then tapered within 1
week), and the patients became afebrile within 1 day.
However, 1 patient (patient 6) had fever recurrence 7
days after the first lymph node biopsy; this fever did
not respond to prednisolone therapy, and the patient
required a second lymph node excision. The other
children showed no fever recurrence during the observation of at least 6 months.
Laboratory Findings
The white blood cell count of all patients indicated
leukopenia (3600 ⫾ 900 per mm3), together with the
normal differential. The mean hemoglobin level was
11.4 ⫾ 1.2 g/dL, which was lower than that of
healthy children of the same age. The erythrocyte
segmentation rate (ESR) was higher (44 ⫾ 18 mm/
hour) than normal, whereas the C-reactive protein
(CRP) level was slightly elevated (1.3 ⫾ 1.1 mg/dL).
The lactate dehydrogenase (LDH) level was increased, although aminotransferase levels were not
increased. The fluorescent antinuclear antibody test
and antirheumatoid factor were negative for all patients. Elevated immunoglobulin G and immunoglobulin E values were noted in 4 of the evaluated
patients (Table 2).
DISCUSSION
KFD is recognized as a distinctive clinicopathologic entity, and it has been well described in the
pathology literature. However, only a few case reports about the disorder are available in the pediatrics literature.11–14,16 KFD is more prevalent in
Asians, particularly in Far East nations including
Korea.5–10 Tanaka et al9 reported that 2 HLA class II
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e753
TABLE 1.
Clinical Characteristics of KFD in Children
Patient
Age/
Gender
Fever Duration,
days
Biopsied Lymph Node
(Size, cm)
Treatment
A*
B†
C‡
1
2
3
4
5
6
8/F
9/M
10/F
11/F
12/M
15/M
5
42
7
7
65
12
10
50
11
9
75
42
4
4
0
0
0
1
Steroid
Steroid
Conservative
Conservative
Conservative
Steroid
0
Cervical (1.0 ⫻ 1.5)
Axillary (0.7 ⫻ 1.0)
Supraclavicular (3.0 ⫻ 4.0)
Cervical (1.3 ⫻ 2.5)
Cervical (2.0 ⫻ 2.5)
Cervical (1.0 ⫻ 1.3 and
3.0 ⫻ 4.0)
Cervical (1.0 ⫻ 1.5)
7
15/M
27
27
8
9
10
11
12
8/F
10/M
6/M
15/M
13/F
15
17
14
10
7
21
24
17
12
18
1
0
1
2
6
Cervical
Cervical
Cervical
Cervical
Cervical
(1.0 ⫻ 0.2)
(1.0 ⫻ 1.5)
(1.5 ⫻ 2.0)
(1.0 ⫻ 1.5)
( 1.0 ⫻ 1.0)
Conservative
Conservative
Conservative
Conservative
Conservative
Conservative
Other
Skin rash
Afebrile before biopsy
Afebrile before biopsy
Relapse
Weight loss, night sweats,
afebrile before biopsy
Afebrile before biopsy
F indicates female; M, male.
* Fever duration before admission.
† Total fever duration before lymph node excision.
‡ Fever duration after lymph node excision biopsy.
genes, the DPA*01 allele and the DPB1*0202 allele,
which is common in Asians but not in whites, might
be related to KFD. In Korea, Koh et al17 reported 24
cases in 1983, and Song et al18 reported the first case
of a pediatric patient in 1990. Although KFD affects
individuals over a wide range of ages, the overall
proportion of pediatric patients has not yet been
defined in the literature. In 1 series, Lin et al10 reported that 21 (34.4%) cases of a total of 61 cases were
pediatric patients ⬍16 years old.
Cervical lymphadenopathy and fever are the most
common presentations of the disorder. However, the
clinical presentation may vary from patient to patient. Some patients with lymphadenopathy complain of malaise, fatigue, night sweats, weight loss,
and gastroenteric symptoms without any fever. Although lymphadenopathy usually affects the cervical
lymph nodes, the axillary lymph nodes and lymph
nodes in other regions can be affected.3–10,14,19 The
size of the affected lymph nodes usually are 2 to 3
cm, but sometimes these nodes can be ⬎5 cm. An
affected lymph node is solid, movable, and painful
but not suppurative. In our series, fever was the
main complaint, and its nature in most patients was
intermittent. Some patients, however, experienced a
daily spiking fever of ⬎40°C for a fairly long period
(patients 2 and 6). Although multiple lymph nodes
were observed in some patients on the affected side
or on both sides of the neck by palpation or sonography, the main affected lymph node was usually
solitary. One patient (patient 2) who presented with
10 days of fever at initial admission did not show any
lymphadenopathy. However, at the second admission, he was eventually noticed to have a lymph
node with tenderness at the right axillary region on
the 40th day of fever. All patients in this series were
observed to have tenderness of the lymph nodes
during the febrile period regardless of the affected
node’s size, suggesting that the fever is associated
with active lymph node inflammation. In evaluating
KFD patients with prolonged fever, a thorough examination of the lymph nodes located in other sites
e754
as well as the palpable regions is warranted.14,19
Hong et al20 in Korea recently reported that among
23 KFD children with cervical lymphadenopathy diagnosed by fine-needle aspiration cytology, lymph
node tenderness was noted in 60% of the patients,
fever was noted in 44%, and the mean age at the time
of presentation was 8.1 ⫾ 3.8 years (range: 14 months
to 14 years). However, almost all patients in this
series presented with fever, tenderness of the lymph
node, and a higher mean age (11 ⫾ 3 years). This
suggested that the immune response and clinical
course of the KFD might differ according to age.
Lymphadenopathy with or without fever is commonly observed in young children and is frequently
overlooked. These findings, along with the self-limited nature of the KFD, suggest that the disease may
be more common than originally thought.
Extranodal involvement rarely occurs in KFD but
includes skin lesions,21 arthritis,22 aseptic meningitis,11,23 and unexpected death.12,24 Two reports independently described that children with KFD experienced a severe clinical course with multiorgan failure
after the use of multiple antituberculous drugs.13,15
The laboratory investigations of KFD revealed leukopenia and anemia. The ESR and LDH levels were
increased, but the transaminase level was unaffected.
Similar to adult data, the laboratory indices of almost
all patients examined in the febrile period showed
leukopenia, anemia, elevated ESR and LDH values,
and normal transaminase values. In addition, a relatively low CRP value and elevated immunoglobulin
G and immunoglobulin E values were noted (Table
2).
The cause of the KFD is unknown. Several infectious agents have been suggested, but none have
been confirmed. The histologic and immunologic
findings together with the typical clinical presentation suggest a hyperimmune reaction of immune
cells to unidentified agents.3,4,25 An autoimmune
contribution to the pathogenesis is suggested by observations showing that the disease can precede or
KIKUCHI-FUJIMOTO DISEASE WITH PROLONGED FEVER IN CHILDREN
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460
2304
1350 ⫾ 1131
1549
2537
1946 ⫾ 496
608–1572
⬃5–45
5–45
⬍0.5
120–330
0–20
150–400
13.5 (11.5–15.5)
Reference*
Hb indicates hemoglobin; AST, aspartate transaminase; ALT, alanine transaminase; IgG, immunoglobulin G; IgE, immunoglobulin E.
* Normal values of children ⬃10 years old.
0–230
2349
285
2175
1522
11
51
32
19
13
19
23
42
27
7
31
16
24 ⫾ 13
18
46
32
32
27
37
25
50
36
21
51
40
35 ⫾ 11
2.6
0.1
1.9
1.5
1.2
1.2
0.3
0.2
0.7
4.0
1.2
0.4
1.3 ⫾ 1.1
358
529
509
773
524
523
298
1191
938
550
819
1036
671 ⫾ 278
220
300
276
263
189
270
288
156
214
333
233
111
238 ⫾ 64
8.6
10.5
12.1
11.4
11.1
11.6
12.0
12.8
11.9
11.9
12.8
10.3
11.4 ⫾ 1.2
3700 (56/31)
4000 (42/43)
4700 (46/38)
3800 (16/64)
2400 (45/43)
4400 (46/42)
3900 (34/57)
2900 (39/55)
3400 (44/48)
4600 (60/30)
3000 (51/39)
1800 (33/66)
3550 ⫾ 890
(43 ⫾ 12/46 ⫾ 12)
8100 (4500–13,500) (54/38)
1
2
3
4
5
6
7
8
9
10
11
12
Mean ⫾ SD
56
56
40
40
21
60
20
34
24
43
45
83
44 ⫾ 18
IgE,
IU/mL
IgG,
mg/dL
ALT,
IU/L
AST,
IU/L
CRP,
mg/dL
LDH,
IU/L
ESR,
mm/h
Platelets,
⫻103 per mm3
Hb, g/dL
WBC, per mm3
(Neutrophil/Lymphocyte, %)
Laboratory Findings of KFD in Children
Patients
TABLE 2.
occur in association with systemic lupus erythematosus.4,7,10,26
A definitive diagnosis of KFD is determined by a
lymph node biopsy. The histopathologic changes in
KFD are known to pass through 3 stages associated
with clinical features.7 The early proliferative stage
with lymphohistocytic proliferation and numerous
atypical mononuclear cells can be confused with a
malignant lymphoma.1,4,27 Tuberculosis, Kawasaki
disease, and systemic lupus erythematosus should
also be differentiated from KFD.
There is no specific therapy for KFD. The majority
of patients show improvement in symptoms and
signs within a few months of presentation. In this
study, 7 of 8 patients became afebrile after the excision biopsy. One patient (patient 5), who had the
longest fever duration in our series and experienced
3 admissions to other hospitals, also improved
quickly after lymph node excision. One patient (patient 6) had left cervical lymphadenopathy and 12
days of fever at his first presentation. After confirming diagnosis by a left lymph node excision biopsy,
he became afebrile for 1 week. He was readmitted
with recurrent fever and right cervical lymphadenopathy. He did not respond to treatment with nonsteroidal anti-inflammatory drugs or prednisolone (1
mg/kg for 7 days). He eventually improved after a
second excision biopsy of the right-side lymph node
(3.0 ⫻ 4.0 cm). These findings suggest that the removal of the affected lymph node is not only diagnostic but also possibly therapeutic. Therefore, even
in cases in which the lymph node excision poses
technical difficulties such as a deep location in the
neck, the removal of the main affected lymph node
may be desirable. A beneficial effect of glucosteroids
has been reported in a small number of cases with
severe or recurrent symptoms.11,28 Although KFD is
a benign disease, the prolonged fever can be distressing to the patient and parents. One patient (patient 6)
described above did not respond to prednisolone.
Although 2 patients (patients 1 and 2) with a recurring fever after a lymph node excision quickly responded to prednisolone treatment, additional study
will be needed for validating steroid treatment for
this disease.
KFD is rare disease, but it should be considered
when making a differential diagnosis of prolonged
fever in children, particularly older children. The
laboratory findings show leukopenia, anemia, elevated ESR and LDH values, and normal transaminases values. An early diagnosis by an excision biopsy of the affected lymph node can help minimize
unnecessary examinations and halt inappropriate or
even harmful treatment and may improve symptoms.
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Kikuchi-Fujimoto Disease With Prolonged Fever in Children
Kyung-Yil Lee, Yeong-Heum Yeon and Byung-Churl Lee
Pediatrics 2004;114;e752; originally published online November 15, 2004;
DOI: 10.1542/peds.2004-0485
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