Clinical characteristics of KFD patients
A total of 20 pediatric patients were enrolled for this study. There were 14 boys and 6 girls (boy: girl = 2.3:1) with a median age of 9.1 ± 3.5 years, and age ranged from 2 to 14 years. Fever and lymphadenopathy were the most common complaints of all patients. Ten patients (50.0%) complained of fever only of three different patterns, including remittent, continued, and intermittent fever. The other ten patients (50.0%) reportedly suffered from both fever and lymphadenopathy. The duration of fever ranged from 6 days to 70 days with a median of 24.2±14.4 days. In these patients, the most frequently involved site was the bilateral cervical lymph node (45.0% of the patients). Notably, all the patients were initially diagnosed with multiple types of diseases, including fever of unknown origin (50%), lymphadenitis (35.0%), sepsis (5.0%), and Epstein-Barr virus (EBV) infection (5.0%) at admission. Interestingly, only one patient (5.0%) was suspected of KFD. Taken together, these findings suggest that the rates of misdiagnoses were relatively high for KFD.
Laboratory findings
Leukopenia (45.0%) was more prominent than leukocytosis (10.0%) in this cohort of 20 cases. Serum inflammatory tests, such as the levels of serum amyloid A (SAA), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) revealed elevated levels in 13 (13/20, 65.0%), 5(5/20, 25.0%) and 17 patients (17/20, 85.0%), respectively. Moreover, serum levels of lactate dehydrogenase (LDH), antistreptolysin O (ASO), and ferritin were also elevated in 16 (16/17, 94.1%), 1 (1/17, 5.9%), and 5 patients (5/15,33.3%), respectively. Furthermore, the liver function tests exhibited abnormally high aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in 38.5% (8/18) and 33.3% (6/18) of cases, respectively. In addition, past EBV infections in 16 patients (16/18, 88.9%) were detected by positive EBV-specific viral capsid antigen (EB-VCA) and nuclear antigen (EB-NA) IgG antibody tests. Interestingly, Pseudomonas aeruginosa appeared in the sputum culture of one patient, and elevated IgE levels were confirmed in 9 patients (9/16, 56.3%). Also, blood culture, cerebrospinal fluid (CSF) routine, bone marrow (BM) morphology examination was subsequently performed and tested negative in some patients. All detailed pathological data are presented in Table 1.
Table 1 Laboratory findings of Kikuchi Fujimoto disease in 20 children.
Positive Findings
|
N (%)
|
Negative Findings
|
N (%)
|
Leukopenia(<4x109)
|
9/20 (45.0%)
|
Blood Culture
|
0/17
|
Neutropenia(<1.5x109)
|
7/20 (35.0%)
|
Cerebrospinal Fluid Routine
|
0/2
|
Leukocytosis(>10x109)
|
2/20 (10.0%)
|
Bone Marrow Morphology
|
0/17
|
SAA >10mg/L
|
13/20(65.0%)
|
TB-PPD
|
0/14
|
CRP >8mg/L
|
5/20(25.0%)
|
Mycoplasma RNA
|
0/19
|
PCT>0.05mg/L
|
0/16(0.0%)
|
TB-IGRA
|
0/19
|
FER >336ng/L
|
5/15(33.3%)
|
G+GM
|
0/12
|
ASO >200KU/L
|
1/17(5.9%)
|
ANA
|
0/15
|
ESR >15mm/h
|
17/20(85.0%)
|
|
|
Sputum Culture
|
1/6(16.7%)
|
|
|
EBV-CA IgG>20
|
16/18(88.9%)
|
|
|
EBV-NA IgG>5
|
16/18(88.9%)
|
|
|
EB-DNA>5000copies
|
1/20(5.0%)
|
|
|
Mycoplasma IgM
|
4/19(21.1%)
|
|
|
LDH>250U/L
|
16/17(94.1%)
|
|
|
AST>40U/L
|
8/18(38.5%)
|
|
|
ALT>50U/L
|
6/18(33.3%)
|
|
|
Elevated IgE
|
9/16(56.3%)
|
|
|
SAA: serum amyloid A; CRP: C-reactive protein; PCT: procalcitonin; ESR: erythrocyte sedimentation rate;; LDH: lactate dehydrogenase; AST: aspartate aminotransferase; ALT: alanine aminotransferase; TB-PPD: purified protein derivative of tuberculin; ANA: anti-nuclear antibody.
Pathological characteristics and immunohistochemical (IHC) analysis
The amounts of acquired specimens were sufficient enough for histopathological diagnosis, and the satisfaction rate of sampling was 100.0% (20/20).All patients had no obvious discomfort and complications. The sizes of lymph node swelling ranged from 15 mm to 34 mm in long diameter with a median of 23.2 mm, and 6-15mm in short diameter with a median of 9.6 mm. The most predominant biopsy sites were the left cervical lymph node (10/20, 50.0%), while other examined sites included the right submaxillary lymph node (1/20, 5.0%), the right inguinal lymph node (1/20, 5.0%), and the right cervical lymph node (8/20, 40.0%). Histopathological features showed extensive apoptosis and degeneration of lymphoid cells with coagulative necrosis and karyorrhetic debris and highly infiltrated macrophages, lymphocytes, crescent histiocytes, and monocytes in the affected lymph nodes. Based on Kuo’s histopathological definition of KFD [4], the histopathological subtype analysis exhibited proliferative type (4/20, 20.0%), necrotizing type (13/20 65.0%), and xanthomatous type (3/20, 15.0%) of lymph nodes in these patients. IHC staining showed that the infiltrated histiocytes were positive for the immune-modulatory markers like CD163 (7/20,35.0%), CD68 (15/20, 75.0%), CD123 (6/15, 40.0%), myeloperoxidase (14/20,70.0%). All the detailed data are presented in Table 2.
Table 2 Pathological immunohistochemical characteristics in 20 children.
Parameters
|
N (%)
|
Sites of US-CNB
|
|
Right submaxillary lymph node
|
1/20 (5.0%)
|
Right Inguinal lymph node
|
1/20 (5.0%)
|
Right cervical lymph node
|
8/20 (40.0%)
|
Left cervical lymph node
|
10/20 (50.0%)
|
Diameter of the lymph node
|
|
Long Diameter (mm)
|
23.2±5.8
|
Short Diameter (mm)
|
9.6±2.6
|
Pathological type
|
|
Proliferative type
|
4/20(20.0%)
|
Necrotizing type
|
13/20(65.0%)
|
Xanthomatous type
|
3/20(15%)
|
Immunohistochemical staining
|
|
CD163
|
7/20 (35.0%)
|
CD68
|
15/20 (75.0%)
|
CD123
|
6/15(40.0%)
|
MPO
|
14/20 (70.0%)
|
Treatment and follow-up
Seven patients (46.7%) were misdiagnosed with an infectious disease and subsequently received combination antibiotic treatments, including cephalosporin and penicillin, before pathological diagnosis. Additionally, all patients were treated with nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and acetaminophen. Seven patients recovered without any specific therapy, as the fever spontaneously disappeared. While other thirteen patients recovered after receiving the low-dose dexamethasone or methylprednisolone for 1-4 weeks. Patients were followed up for 1 to 4.5 years. All patients had a good prognosis. None of the patients developed systemic lupus erythematosus (SLE) or malignant lymphoma during the follow-up period. Unfortunately, recurrence occurred in 3 patients (3/20, 15.0%) after six months to one year from the first episode. Histopathological diagnosis to prove recurrence was performed in one patient by excisional biopsy while the remaining two patients had a clinical recurrence, and corticosteroids therapy remained effective for them.