Tropical medicine rounds

Japanese spotted fever with acute hepatic failure: was it

associated with Epstein-Barr virus?

Makoto Kondo1, MD, Ichiro Kurokawa2, MD, Kei-ichi Yamanaka2, MD,Shigehiro Akachi3, MD, and Masami Nishii1, MD

1Department of Dermatology, Ise

Municipal General Hospital, Ise, Mie,

Japan, 2Department of Dermatology,

Mie University Graduate School of

Medicine, Tsu, Mie, Japan, and 3Mie

Prefecture Health and Environment

Research Institute, Yokkaichi, Mie,

Japan

Correspondence

Makoto Kondo, MD

Department of Dermatology

Ise Municipal General Hospital

3038 Kusube-cho

Ise, Mie 516-0064

Japan

E-mail: pjskt886@ybb.ne.jp

The authors report no conflicts of

interest.

Abstract

Background An 81-year-old female experiencing high fever, fatigue, and loss of appetite

was admitted to our hospital and diagnosed with acute cholecystitis. Her condition did not

improve and an eschar and erythema subsequently appeared. We then diagnosed Japa-

nese spotted fever (JSF). She recovered immediately after the administration of

minocycline. This case differed from other cases because the patient had a remarkably

acute hepatic failure.

Methods Considering that the present case might be associated with other factors, we

performed a repeat polymerase chain reaction (PCR) test on the patient’s blood that had

been collected on admission and stored.

Results Epstein-Barr virus (EBV) was detected in her blood by PCR.

Conclusion We consider this case might be associated with EBV.

Introduction

Japanese spotted fever (JSF) is caused by Rickettsia japon-

ica. Delayed diagnosis of JSF may lead to multiple organfailure (MOF)1 and fatal2,4 and deceased2 cases. Wereport a case of JSF in which R. Japonica and Epstein-Barr virus (EBV) were detected by polymerase chain reac-tion (PCR) and showed acute hepatic failure more thancases with MOF1, fatality,2,4 or death2.

Case report

An 81-year-old female had high fever. Fatigue and appe-tite loss gradually developed and revealed no appreciabledisease. She was admitted to our hospital five days afteronset of symptoms. Laboratory findings revealed acutehepatic failure, acute renal failure and an inflammatoryresponse (Table 1). She was diagnosed with acute chole-cystitis and treated with an intravascular beta-lactamaseinhibitor, sulbactam/cefoperazone (SBT/CPZ), but heracute hepatic failure and renal failure did not improve.Two days after admission, erythema began to appear(Fig. 1), and an eschar was noticed on her left cheek

(Fig. 2). Therefore, we suspected JSF and intravascularminocycline treatment was started immediately. PCR forR. japonica was performed at Mie Prefecture Healthand Environment Research Institute because of the defi-nite diagnosis of JSF, and a positive PCR result wasobtained for the skin lesion and eschar. Her general con-dition markedly improved. Thirteen days after admis-sion, laboratory findings were within normal limits,except for alkaline phosphatase (ALP) (Table 1). Sheunderwent rehabilitation for muscle weakness and wasdischarged 25 days after admission. Of the 17 cases ofJSF studied from 2008 to 2009, the present case showedmarkedly more acute hepatic failure. Therefore, we com-pared this case with published cases of JSF. Our patientshowed more acute hepatic failure than other patients,including those with MOF and those who have died.Considering that the present case might be associatedwith other factors, we performed a repeat PCR test onthe patient’s blood that had been collected on admissionand stored at Mie Prefecture Health and EnvironmentResearch Institute. PCR was positive for EBV. We sus-pected that EBV might be associated with acute hepaticfailure in this case. PCR was negative for herpes simplex 1403

ª 2010 The International Society of Dermatology International Journal of Dermatology 2010, 49, 1403–1405

virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), cyto-megalovirus (CMV), varicella zoster virus (VZV), humanherpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7),human herpesvirus-8 (HHV-8), and scrub typhus.

Discussion

As reported by published cases of JSF, delayed diagnosisof JSF may lead to MOF1 and fatal,2,4 deceased2 cases.Severe cases of JSF showed elevation of liver enzymes(AST/ALT) to about 200 IU/l. Most cases of JSF showedslight liver enzyme elevation.3,4 Nonetheless, five daysafter onset, our patient had acute hepatic failure. If shehad only acute cholecystitis, SBT/CPZ should have beeneffective. However, her acute hepatic failure did notimprove after two days of SBT/CPZ treatment, thoughher CRP level decreased. Abdominal computed tomo-graphic scanning and echo showed almost normal liverand cholecystis. Immediately after minocycline treatmenther laboratory findings improved and temperature nor-malized. PCR results indicated that she had JSF. Herinflammatory response decreased after administratingSBT/CPZ. Erythema appeared on her body 7 days afteronset. Why did these unexpected events occur? We con-sidered them to be associated with EBV, which wasdetected in her blood by PCR. EBV is a resident virusand most people show latent infection with no apprecia-ble disease. However, some EBV-infected people showinfectious mononucleosis, chronic active EBV infection,malignant lymphoma, cancer, and other conditions. EBVis also associated with chronic fatigue syndrome. We sus-pected that she might have experienced some events asso-ciated with EBV infection. First, EBV was reactivatedafter which she developed antecedent EBV infection.Moreover, she developed a complicated infection withJSF after her EBV infection. She had acute hepatic failure.In fact, she was infected with JSF a few days after onsetand erythema appeared subsequently. Consequently, wemisunderstood that late erythema appeared 7 days afteronset. Her decreased CRP level was not an antibacterialFigure 2 Eschar on the left cheek

Figure 1 Watery erythema seen 7 days after onset

Table 1 Blood examination

The day

after

admission

WBC

(/ll)

CRP

(mg/dl)

AST

(IU/l)

ALT

(IU/l)

LDH

(IU/l)

ALP

(IU/l)

c-GTP

(IU/l)

T-Bil

(mg/dl)

CPK

(IU/l)

BUN

(mg/dl)

Cre

(mg/dl)

PLT

(X104/ll)

FIB

(lg/ml)

FDP

(lg/ml)

1 11 600 25.16 845 179 672 1709 N.D 2.2 N.D 81.9 3.81 6.4 N.D N.D

3 13 000 8.94 965 216 635 1468 94 1.9 N.D 89.1 3.57 6.9 268 N.D

5 11 300 3.41 305 128 333 1176 102 1.7 20 44.9 1.76 11.7 N.D 3.4

10 10 000 1.98 71 56 296 927 99 2.0 30 15.9 0.63 27.1 N.D N.D

13 6600 0.91 33 30 239 696 66 1.5 N.D 14.2 0.60 31.1 N.D N.D

20 5100 <0.3 27 15 N.D 460 45 0.8 N.D N.D N.D 20.8 N.D N.D

N.D, not done.

International Journal of Dermatology 2010, 49, 1403–1405 ª 2010 The International Society of Dermatology

Tropical medicine rounds Japanese spotted fever with acute hepatic failure Kondo et al.1404

effect of SBT/CPZ, but EBV infection spontaneouslyregressed. This hypothesis may not be valid because theevidence that EBV became reactivated was insufficientevidence in the only result of EBV detected by PCR. Sec-ond, she had acute hepatic failure because she was immu-nocompromised. Patients who do not show erythema orwho show late erythema are rarely reported.4 She wasdiagnosed with antecedent EBV infection, and the EBVgene was detected accidentally in her blood by PCR. CRPis a protein synthesized in the liver, and acute hepaticfailure results in decreased capacity to produce CRP.Third, the first and second hypotheses could be combined.This case differed in clinical course and laboratory andclinical findings from the JSF case we experienced previ-ously. We assume that JSF patients would show someeffect of EBV if JSF leads to acute hepatic failure in acomparatively short time. EBV is one of the virusesresponsible for chronic fatigue syndrome and leads to animmunocompromised state. Lymphoproliferative disorderhas been identified as positive for EBV.5 The disease canoccur even in apparently healthy, elderly persons. Theimmunocompromised state is presumed to be associated

with B-cell reactivation and EBV positivity. Our patientwas elderly and might have had acute hepatic failurebecause of being immunocompromised by EBV. We sup-port the second hypothesis. In conclusion, we considerthat this case might be associated with EBV.

References

1 Kodama K, Senba T, Yamauchi H, et al. Japanese spottedfever associated with multiorgan failure. J Infect

Chemother 2001; 7: 247–250.2 Nomura T, Fujimoto T, Ebisutani C, et al. The first fatal

case of Japanese spotted fever confirmed by serological andmicrobiological tests in Awaji Island, Japan. Jpn J Infect

Dis 2007; 60: 241–243.3 Mahara F. Japanese spotted fever: report of 31 cases and

review of the literature. Emerg Inf Dis 1997; 3: 105–111.4 Kondo M, Nishii M, Kurokawa I, et al. Nine cases of

Japanese Spotted Fever diagnosed at our hospital in 2008.Int J Dermatol 2010; 49: 430–434.

5 Oyama T, Ichimura K, Suzuki R, et al. Senile EBV+ B-celllymphoproliferative disorders: a clinicopathologic study of22 patients. Am J Surg Pathol 2003; 27: 16–26.

ª 2010 The International Society of Dermatology International Journal of Dermatology 2010, 49, 1403–1405

Kondo et al. Japanese spotted fever with acute hepatic failure Tropical medicine rounds 1405