An atypical presentation of Kikuchi-Fujimoto disease mimicking systemic lupus erythematosus: case report and literature review

doi:10.4236/ojped.2011.14016

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Open Journal of Pediatrics, 2011, 1, 67-71

doi:10.4236/ojped.2011.14016 Published Online December 2011 (http://www.SciRP.org/journal/ojped/ OJPed

)

Published Online December 2011 in SciRes. http://www.scirp.org/journal/OJPed

An atypical presentation of Kikuchi-Fujimoto disease

mimicking systemic lupus erythematosus: case

report and literature review

Diane Belder-Preston1*, Catherine-Maude Pound1,2, Roman Jurencak1,3

1Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, Canada;

2Division of Pediatric Medicine, Children’s Hospital of Eastern Ontario, Ottawa, Canada;

3Division of Rheumatology, Children’s Hospital of Eastern Ontario, Ottawa, Canada.

Email: *[email protected]

Received 1 October 2011; revised 5 November 2011; accepted 18 November 2011.

ABSTRACT

Purpose: To report a case of atypical Kikuchi-Fuji-

moto disease (KFD) that illustrates several overlap-

ping features with systemic lupus erythematosus

(SLE). Methods: A case is reported followed by a re-

view of the current literature. Case Report: A 16- year-

old boy with an unusual manifestation of Kikuchi-

Fujimoto disease (KFD) is described. The patient

presented with fever, weight loss and severe abdomi-

nal pain, due to extensive necrotizing retroperitoneal

and mesenteric lymphadenopathy. During the course

of his illness, he developed several symptoms sugges-

tive of systemic lupus erythematosus (SLE): a peri-

cardial effusion, cotton wool spots on the retina and

antibodies against nuclear antigens (ANA), Smith

(Sm) and ribonucleoprotein (RNP) antigens. However,

no additional features of SLE were found. The pa-

tient subsequently fully recovered within two months,

without initiation of immunosuppressive therapy. His

autoantibodies became negative five months after

initial presentation and he remains well at his 23

month follow up visit. Discussion: We hypothesize

that the autoantibodies developed by our patient

were secondary to self-antigen induced autoimmunity

related to his extensive tissue necrosis. Despite ini-

tially having clinical features suggestive of SLE, our

patient’s full and spontaneous recovery strongly

supports the diagnosis of KFD. This illustrates the

need for careful diagnosis, in order to avoid unneces-

sary and potentially toxic treatment with immuno-

suppressive agents.

Keywords: Kikuchi-Fujimoto’s Disease; Retroperitoneal

Lymphadenitis; Systemic Lupus Erythematosus (SLE);

Antinuclear Antibodies (ANA)

1. INTRODUCTION

Kikuchi disease, also called Kikuchi-Fujimoto Disease

(KFD) and Histiocytic Necrotizing Lymphadenopathy, is

a rare, benign, self-limited disease of unknown etiology.

KFD was first reported in 1972 by Kikuchi [1] as well as

independently, by Fujimoto et al. [2]. Typical features of

the disease include subacute regional lymphadenopathy

predominantly involv ing cerv ical lymph nodes as well as

fevers, often accompanied by leukopenia, high erythro-

cyte sedimentation rate (ESR), and anemia [3]. Exci-

sional biopsy of the affected lymph node shows non-

specific histopathologic features of cortical and paracor-

tical necrosis. No specific diagnostic imaging or labora-

tory tests are available and KFD remains a diagnosis of

exclusion. Clinicians must rule out other causes of ne-

crotizing lymphadenopathy, such as malignancy, sys-

temic connective tissue disorders, and infectious lym-

phadenitis, before diagnosing KFD. These other diagno-

ses have different therapeutic and prognostic implica-

tions. This can result in costly and invasive investiga-

tions, potentially causing significant distress to the pa-

tient and family.

We describe the case of a young man who presented

to a pediatric tertiary care centre with atypical features

of Kikuchi-Fujimoto Disease.

2. CASE REPORT

A 16-year-old, previously healthy, Caucasian boy pre-

sented to a pediatric tertiary care centre with a three-

week history of intermittent abdominal pain, vomiting,

anorexia and a seven-kilogram weight loss. He also had

a two-week history of intermittent fevers, up to 40 de-

grees Celsius, associated with a faint diffuse erythema-

tous rash involving the face and upper torso. Personal

and family histories were noncontributory.

Physical examination on admission revealed a pale,

D. Belder-Preston et al. / Open Journal of Pediatrics 1 (2011) 67-71

thin boy, weighing 59.7 kg. His vital signs were: heart

rate 120, blood pressure 121/81, respiratory rate 16 and

oxygen saturation 98% in room air. He was afebrile with

a faint malar flush. His abdomen was non-acute but dif-

fusely tender with no hepatosplenomegaly. The remain-

der of the examination was unremarkable. No peripheral

lymphadenopathy was appreciated.

Laboratory investigations showed elevated inflamma-

tory markers, mild non-hemolytic anemia, transaminitis

and markedly elevated lactate dehydrogenase (LDH)

(Table 1). Autoantibodies (anti-nuclear antibodies (ANA),

anti-neutrophil cytoplasmic antibodies, rheumatoid fac-

tor and antiphospholipid antibodies) were all negative.

Complement (C3, C4) and total immunoglobulin levels

(IgG, IgA and IgM) were within normal limits.

A Computerized Tomography scan of his abdomen

demonstrated significant lymphadenopathy in both the

retroperitoneum and the root of the mesentery. Explor-

ative laporotomy with lymph node biopsy showed ne-

crotizing lymphadenitis with extensive tissue necrosis,

without evidence of neutrophilic inflammation or pres-

ence of granulomas. In one section, a vessel with intra-

mural chronic inflammation suspicious for vasculitis was

observed. Special stains for infectious organisms and

immunophenotyping for neoplastic cells yielded nega-

tive results.

Given the absence of a definitive diagnosis, further

investigations were performed. These included bone

marrow studies to rule out malignancy, upper and lower

endoscopies with biopsies to rule out atypical inflam-

matory bowel disease and Whipple’s disease, as well as

an extensive infectious work up. Tuberculosis, Epstein-

Barr virus, toxoplasmosis, parvovirus, cytomegalovirus,

Streptococcus pneumonia, and fungal infections were

excluded. Ophthalmologic examination uncovered mul-

tiple retinal cotton wool spots. Cardiac echocardiogra-

phy demonstrated a moderate-sized pericardial effusion

with no hemodynamic compromise. Magnetic Reso-

nance Angiography of the abdomen, as well as a Mag-

netic Resonance Imaging of the hip and shoulder girdles

helped to exclude the diagnoses of vascu litis and myosi-

tis.

During his hospitalization, our patient received mainly

supportive care after a brief three-day course of a third

generation cephalosporin antibiotic pending negative

cultures. The severity of his abdominal pain was such

that he required morphine, gabapentin, ketorolac and

clonidine. Because of poor ap petite, food intoleran ce and

ongoing weight loss, total parenteral nutrition was initi-

ated.

Atypical Kikuchi-Fujimoto disease was suspected

based on the presence of necrotizing non-granulomatous

retroperitoneal lymphadenitis and the exclusion of other

disorders. Intravenous immunoglobulin therapy was

offered but declined by the patient’s family. Steroid

therapy was not offered as there was still a degree of

uncertainty in terms of the diagnosis of KFD at that

stage.

With supportive management only, the patient’s clini-

cal status improved. By day 30 of hospitalization, he was

ambulating, tolerating increasing naso-gastric feeds and

demonstrating consistent weight gain. At the family’s

request, the patient was transferred to another tertiary

care centre for a second opinion.

At the second hospital, approximately one month after

his initial biopsy, the patient underwent another laporo-

tomy with lymph node biopsy. Extensive bland necrosis

with numerous macrophages was reported. Histiocytes,

lymphocytes and minor plasma cell populations were

scattered throughout. Again, no neutrophilic infiltration

Table 1. Laboratory data.

Reference range During admission Eight weeks after admission Five months after admission

ESR (mm/Hr) 0 - 10 63 13 6

CRP (mg/L) <8.0 15 < 1 <1

Ferritin (ug/L) 24 - 336 1408 968

WBC (×109 L) 4.5 - 11 10.6 4.85 4.5

Hb (g/L) 120 - 160 90 129 153

Plt (×109 L) 150 - 450 382 393 229

AST (U/L ) 14 - 50 265 19 26

ALT (U/L) 10 - 55 143 17 20

LDH (U/L) 300 - 700 3016 399 468

ESR, erythrocyte sedimentation rate; CRP, C reactive protein; WBC, White blood cell; Hb, Hemoglobin; Plt, Platelet; AST, Aspartate aminotransferase; ALT,

lanine transaminase; LDH, lactate dehydrogenase. A

D. Belder-Preston et al. / Open Journal of Pediatrics 1 (2011) 67-71 69

or granuloma was seen. Absence of hematoxylin bodies

was noted. No infectious etiology was identified. On

repeat testing, some of the patient’s autoantibodies and

immunoserologies became positive (Table 2). Labora-

tory methods used to detect these autoantibodies were

identical at both hospitals (ANA by indirect immuno-

fluorescence using Hep-2 cell line as substrate, ENA by

ELISA). Nonetheless, he continued to improve with

supportive treatment only, and no immunosuppressive

therapy was initiated. There was full resolution of his

pericardial effusion, and disappearance of the cotton

wool spots on his retina.

The patient was discharged home with a presumed

diagnosis of KFD. He now remains completely asymp-

tomatic 23 months after hospital discharge. His previ-

ously abnormal inflammatory markers and positive im-

munoserologies have completely normalized (Tables 1

and 2).

3. DISCUSSION

In this report, we present a case of atypical KFD with

retroperitoneal lymph node involvement and several

features initially suggestive of SLE.

Most of the literature on KFD comes from the adult

population, with the exception of several case series and

reports published in the pediatric literature [3-10]. Young

adults are predominantly affected, with a reported mean

age of 25 years, as shown by a meta-analysis of 181

worldwide publications looking at 244 patients [7].

Cases have however been reported in all age groups,

ranging from 19 months to 75 years [11]. Two recent

pediatric case series, one from Korea [6] and the other

from Taiwan [5], reported a mean age of 11 and 12.8

years respectively. Historically, there has been a higher

predilection for young women, although a recent com-

prehensive review reported a ratio closer to 1:1 [11]. In

the pediatric population, the ratio seems to be higher in

boys with reported ratios ranging from 1.4 to 2.8:1 [5,

6].

KFD typically presents with cervical lymphadenopa-

thy. Low-grade fevers, fatigue, skin rashes affecting the

face and the upper body, nausea, vomiting, diarrhea and

weight loss are also reported [7,9,11]. Cases of non-cer-

vical lymphadenopathy have been described; generalized,

axillary, iliac and retroperitoneal lymphadenopathy (re-

ported in 0 to 3% of cases) [4,12,13]. Rimar et al. [14]

retrospectively reviewed 19 cases of possible KFD from

seven medical centers in Israel between 1980 and 2007.

In their study, a much higher rate of retroperitoneal and

generalized lymphadenopathy was reported as compared

to the rate reported in previous Far East studies. They

found that 21% and 26% of cases presented with retro p-

eritoneal and generalized lymphadenopathy, respec-

tively.

Our patient presented with severe necrotizing ab-

dominal lymphadenopathy without other lymph node

involvement. Moreover, during the course of his illness,

he developed several features suggestive of SLE (retinal

vasculitis with cotton wool spots, small pericardial effu-

sion and positive ANA, anti-Sm and anti-RNP antibod-

ies). There are several case reports discussing an asso-

ciation between KFD and SLE [7,15-18] and some pos-

tulating KFD as a self-limited SLE-like autoimmune

condition [19].

Our patient developed an autoantibody profile highly

suggestive of SLE. However, his autoantibodies were

positive only transiently and normalized within four

months, without the need for immunosuppressive ther-

apy. We hypothesize that the extensive necrotizing lym-

phadenopathy led to a release of self-antigens which, in

Table 2. Autoantibody t esting.

On admission Five weeks into the admission Four months after initial positive r e s u l t s

ANA Negative Positive Negative

ANA titer - 1:160 -

Anti-double stranded DNA - Negative Negative

ENA screen Negative Positive Negative

Anti Smith - Positive Negative

Anti RNP - Positive Negative

Anti Scl 70 - Negative Negative

Anti Ro - Negative Negative

Anti La - Negative Negative

NA, Anti-nuclear antibodies; RNP, Anti-ribonucleoprotein antibodies; ENA, Extractable Nuclear Antigens.

D. Belder-Preston et al. / Open Journal of Pediatrics 1 (2011) 67-71

the hyperinflammatory state, enabled mounting of a

pathologic immune response with production of autoan-

tibodies. Upon removal of the antigenic stimulation, the

pathologic production of autoantibodies ceased, leading

to their disappearance from the circulation. This hy-

pothesis is supported by the fact that, 23 months after

initial presentation, the patient remains off any therapy

and healthy.

Cotton wool spots, which were ob ser v ed in our patien t,

often indicate a serious systemic disease. They represent

acute, focal, inner retinal ischemia and may occur in any

disease that compromises arteriolar circulation to the

inner retinal layers which includes SLE and systemic

vasculitides where ischemia is caused by thrombogenic

effects from antigen-antibody complexes [20]. However,

similar to our patient, isolated, self-limited cotton wool

spots in patients with no identifiable systemic disease

have also been reported [21].

The presence of pericardial effusion in our patient

could indicate SLE as pericarditis is the most common

cardiac manifestation of this disease. However, transient

asymptomatic pericardial effusions are often seen in

instances of significant systemic inflammation, espe-

cially in the presence of accompanying hypoalbumine-

mia [22]. Our patient did have hypoalbuminemia (data

not shown). The pericardial effusion in our patient was

asymptomatic with spontaneous resolution. Pericarditis

accompanying KFD has not been previously described.

Histologically, SLE and KFD can be very challenging

to differentiate and at times impossible. In KFD, histo-

pathological findings include varying degrees of necrosis,

histiocytic proliferation with activated T lymphocytes,

small lymphocytes and plasma cells without granuloma-

tous inflammation with absent neutrophils and eosino-

phils. Adjacent vessels may be thrombosed. In contrast

to KFD, SLE lymphadenitis, demonstrates hematoxylin

bodies (aggregates of degenerated nuclear debris) and

Azzopardi phenomenon (degenerated nuclear material

aggregated in the walls of blood vessels). In SLE, abun-

dant plasma cells, prominent reactive follicular hyper-

plasia, sparse cytoxic T cells and capsular and pericap-

sular inflammation are seen [23,24]. In our patient’s bi-

opsy specimens, the presence of extensive necrosis

without neutrophilic inflammation or granulomas and

the absence of hematoxylin bodies support the diagnosis

of KFD rather than SLE or systemic vasculitis.

In conclusion, this report discusses a case of atypical

KFD and illustrates several overlapping features of KFD

and SLE. Our patient presented with retroperitoneal

lymphadenopathy, an unusual manifestation of KFD. He

demonstrated a transient elevation of autoantibodies

typically associated with SLE, as well as retinal vascu-

litis and pericardial effusion, not previously described in

patients with KFD. This illustrates the need for careful

differential diagnosis, as KFD is self-limited and, con-

trary to SLE, does not require long-term immunosup-

pressive therapy; ra ther, often only supportive ther apy is

needed.

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ABBREVIATIONS

Kikuchi-Fujimoto disease (KFD),

Systemic lupus erythematosus (SLE),

Antinuclear antibodies (ANA),

lactate dehydrogenase (LDH),

erythrocyte sedimentation rate (ESR),

smith (Sm),

ribonucleoprotein (RNP),

C reactive protein (CRP),

White blood cell (WBC),

Hemoglobin (Hb),

Platelet (Plt),

Aspartate aminotransferase (AST),

Alanine transaminase (ALT).