e124 • CID 2004:39 (15 December) • BRIEF REPORT

B R I E F R E P O R T

Kikuchi-Fujimoto Disease:Hydroxychloroquine as a Treatment

Katayoun Rezai,1,2 Sandesh Kuchipudi,2 Vishnu Chundi,4 Reshma Ariga,3

Jerome Loew,3 and Beverly E. Sha2

1Section of Infectious Diseases, Department of Medicine, John H. StrogerHospital of Cook County, 2Section of Infectious Diseases, Department ofMedicine, and 3Department of Pathology, Rush University Medical Center,and 4Metro Infectious Disease Consultants, Chicago, Illinois

We describe a case of recurrent Kikuchi’s disease in a South

Asian–American man that was treated successfully with chlo-

roquine and on recurrence with hydroxychloroquine. Each

treatment led to a very prompt response.

Case report. A 26-year-old South Asian–American man pre-

sented with a 1-month history of fever, chills, fatigue, weight

loss (of 2.26 kg), and bilateral cervical adenopathy. Symptoms

began with daily low-grade fever and small oral aphthous ul-

cers, which progressed to protracted high-grade fever, rigors,

and bilateral cervical adenopathy. The patient received empiric

courses of azithromycin and amoxicillin/clavulanate acid, but

there was no response. He eventually developed nonbloody

diarrhea, fever with a temperature as high as 40.7�C, dry cough,

and night sweats. No other lymph nodes were enlarged, and

he did not complain of neck pain, headaches, or a rash. An

outpatient diagnostic workup, including serologic testing for

syphilis and systemic lupus erythematosus (SLE), did not yield

a diagnosis, and the patient was eventually hospitalized after a

near-syncopal event.

The patient did not have a significant medical history, and

he had no history of drug abuse. He had traveled to India 1

year prior to the development of symptoms. He did not receive

treatment with prophylactic antimalarials before or during the

trip. In India, the patient developed fever and chills that lasted

4 days and that resolved after treatment with a course of tet-

racycline. On physical examination, his temperature was 40�F.

Findings of the examination were normal, except for the pres-

Received 15 July 2004; accepted 1 September 2004; electronically published 21 November2004.

Reprints or correspondence: Dr. Katayoun Rezai, Section of Infectious Diseases, Cook CountyHospital (John H. Stroger), 637 S. Wood #124, Durand Bldg., Chicago, IL 60612(Krezai@rush.edu).

Clinical Infectious Diseases 2004; 39:e124–6� 2004 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2004/3912-00E1$15.00

ence of 2 nontender, soft, mobile lymph nodes (size, 1 � 1.5

cm) in the right anterior cervical triangle and 1 nontender, soft,

mobile lymph node (size, cm) in the left posterior cervical2 � 3

triangle. Findings of the ear, nose, and throat examination were

otherwise unremarkable. Fevers and chills persisted for 2 weeks

despite treatment with broad-spectrum antibiotics. Treatment

with antibiotics was eventually discontinued because of the

possibility of drug-fever, without effect. The patient underwent

a bone marrow biopsy and lymph node biopsy and, pending

the results of both biopsies, received treatment with chloro-

quine for possible malaria infection. Blood smears for malaria

organisms were negative. Within 8 h of his first dose of chlo-

roquine, the patient’s fever completely resolved. He completed

4 days of treatment with chloroquine, which was followed by

14 days of treatment with primaquine for possible malaria.

After the patient’s hospital discharge, his bone marrow bi-

opsy specimen revealed a normocellular marrow with mildly

megaloblastoid erythropoiesis and slight eosinophilia. No tu-

mors or granulomas were seen. The peripheral blood smear

appeared normal. The cervical lymph node architecture was

effaced by well defined nodular infiltrates composed of a mix-

ture of plasmacytoid monocytes, immunoblasts, small lym-

phocytes, histiocytes with twisted and crescentic nuclei, and

abundant karyorrhectic debris, but no neutrophils. The his-

tologic features were consistent with necrotizing lymphadenitis

or Kikuchi-Fujimoto disease.

The patient was healthy until 1 year later, when he developed

similar symptoms, including low-grade fever that progressed

to high-grade fever (with a temperature of 40�C) and right-

side cervical adenopathy. After 1 week of worsening symptoms,

he underwent a lymph node biopsy, the findings of which were,

again, consistent with Kikuchi-Fujimoto disease (figures 1 and

2). Because of the patient’s prior history, a course of hydroxy-

chloroquine (at a dosage of 200 mg twice per day orally for 14

days) was prescribed. His fever resolved again within 8–10 h

after administration of the first dose. Serologic testing was neg-

ative for SLE. His condition remained good throughout the next

14 months.

Discussion. Kikuchi-Fujimoto disease was first described

in 1972 by Kikuchi and Fujimoto in Japan [1]. They described

a benign, self-limited syndrome of necrotizing lymphadenitis

with distinctive histologic findings. The clinical symptoms are

nonspecific and generally include cervical adenopathy and fe-

ver with a combination of other associated symptoms consist-

ing of chills, sweats, malaise, nausea, vomiting, diarrhea, weight

loss, fatigue, arthralgias, myalgias, hepatomegaly, and/or sple-

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Figure 1. Low-power micrograph of a cervical lymph node biopsy specimen reveals that lymph node architecture is effaced by well-defined nodularinfiltrates (hematoxylin-eosin stain; original magnification, �100).

nomegaly [2]. Up to 30% of patients with Kikuchi-Fujimoto

disease may also have cutaneous manifestations, such as mor-

biliform, drug eruption-like, rubella-like, urticarial, maculo-

papular, or erythematous rashes [3]. The disease was first re-

ported in Asians; it has since been reported in persons of all

races and ethnicities [1]. Most individuals with the disease are

!30 years of age; however, patients of 11–80 years of age have

been reported.

There are no specific diagnostic laboratory tests to confirm

the diagnosis of Kikuchi-Fujimoto disease. Neutropenia, lym-

phocytosis, abnormal liver enzyme levels, an elevated lactate

dehydrogenase level, and an elevated sedimentation rates have

been reported [2]. The diagnosis is based on the presence of

typical clinical symptoms and a lymph node biopsy specimen

showing distinctive histologic features, which include patchy

circumscribed necrosis with prominent karyorrhexis, bordered

by histiocytes and transformed lymphoid cells [1].

The etiology of the disease is unknown. Viruses such as

Epstein-Barr virus, parainfluenza virus, and human herpes vi-

rus type 6 have been implicated as causes, but culture and

special staining have not confirmed these associations. Others

have postulated that the disease may represent a hyperimmune

response to various microbial, chemical, physical, or neoplastic

agents [2].

The differential diagnosis of this disease includes tubercu-

losis, SLE, sarcoidosis, and lymphoma. The histopathologic

findings, at times, can be mistaken for those characteristic of

SLE. There have been case reports of Kikuchi-Fujimoto disease

preceding the onset of, occurring simultaneously with, or oc-

curring during the evolution of SLE [4].

The disease is usually benign and self-limited. No specific

treatment has been reported to be effective. Resolution of the

symptoms typically occurs within 1–4 months. Three to 4 per-

cent of Kikuchi-Fujimoto disease patients experience 1 or more

recurrent episodes. Treatment with nonsteroidal anti-inflam-

matory agents has been used to control symptoms. Therapy

has been focused on patients with recurrent disease or severe

symptoms. Jang et al. [5] administered glucocorticoids to 3

patients who had recurrent or prolonged symptoms, and ob-

served a good response. Glucocorticoids have also been used

alone or in combination with hydroxychloroquine to treat pa-

tients with SLE and Kikuchi-Fujimoto disease. Vila et al. [4]

described a patient who presented with Kikuchi-Fujimoto dis-

ease 10 months prior to the development of SLE manifestations.

This patient did not receive therapy at the time of presentation

of Kikuchi-Fujimoto disease; however, he was treated with

prednisone and hydroxychloroquine when SLE was diagnosed

[4]. Similar cases—involving patients who have received di-

agnoses of Kikuchi-Fujimoto disease and SLE and who have

responded to treatment with glucococorticoids and hydroxy-

chloroquine—have been reported by Litwin et al. (6), Tumiati

(7), and Bousquet et al. (8).

The patient described here is unique. After 14 months of

follow-up there were no signs of SLE. To our knowledge, this

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Figure 2. High-power micrograph of cervical lymph node tissue reveals that the infiltrate is composed of a mixture of plasmacytoid monocytes,immunoblasts, small lymphocytes, histiocytes with twisted and crescentic nuclei, and abundant karyorrhectic debris, but no neutrophils (hematoxylin-eosin stain; original magnification, �400).

is the first report of a case in which hydroxychloroquine was

used to treat a patient with recurrent Kikuchi-Fujimoto disease

without the presence of another inflammatory process, such as

SLE. During the patient’s first episode, chloroquine was used

to treat possible malaria. Because of the patient’s impressive

response, we chose to use hydroxychloroquine to treat his sec-

ond episode of Kikuchi-Fujimoto disease. We postulate that the

anti-inflammatory effects of hydroxychloroquine led to the im-

provement of his condition. We propose the use of hydroxy-

chloroquine as an alternative treatment for Kikuchi-Fujimoto

disease, given its superior safety profile, compared with that of

glucocorticosteroids.

Acknowledgment

Potential conflicts of interest. All authors: no conflicts.

References

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3. Seno A, Torigoe R, Shimoe K. Kikuchi’s disease (histiocytic necrotizinglymphadenitis) with cutaneous involvement. J Am Acad Derm 1994;30:504–6.

4. Vila LM, Mayor AM, Silverstrini IE. Therapeutic response and long-term follow-up in a systemic lupus erythematous patient presentingwith Kikuchi’s disease. Lupus 2001; 10:126–8.

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