Jpn. J. Infect. Dis., 60, 2007

Laboratory and Epidemiology Communications

The First Fatal Case of Japanese Spotted Fever Confirmed by
Serological and Microbiological Tests in Awaji Island, Japan
Tetsuhiko Nomura, Tsuguto Fujimoto1*, Chikara Ebisutani, Hidehisa Horiguchi and Shuji Ando1
Hyogo Prefectural Awaji Hospital, Hyogo 656-0013, andNational Institute of Infectious Diseases, Tokyo 162-8640, Japan

1

Communicated by Ichiro Kurane(Accepted June 4, 2007)

Japanese spotted fever is an important rickettsial diseasein Japan (1). Japanese spotted fever was first reported byMahara et al. (2,3) in 1984 in Anan City, Tokushima Prefecture, Japan. Since then, cases of Japanese spotted fever havebeen reported in many regions of the country. Yuzuruha Mountain in Awaji Island (Figure 1) is one of the areas heavily
contaminated with Rickettsia japonica, and Japanese spotted

fever cases are reported every summer in this area (4). In thepresent report, we describe the first fatal case of Japanesespotted fever confirmed by serological and microbiologicalmethods.
A 77-year-old male recognized loss of appetite as the initial symptom on September 2, 2005, which is defined as day
1 of his illness. Rash appeared on the lower thighs on day 2,and a high fever of 38.7°C, dysarthria, and gait disorder on
day 4. The patient visited Awaji hospital on day 6, because
the symptoms had worsened. The patient claimed that he had
worked on farmland, but had not visited a forested area
before he developed the illness. He was alert on arrival at the*Corresponding author: Mailing address: Infectious Disease Surveillance Center, National Institute of Infectious Diseases, 123-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan. Tel: +81-35285-1111, Fax: +81-3-5285-1129, E-mail: fujimo-t@nih.go.jp241

R2 primer combination to detect spotted fever group rickettsia, and a 2nd PCR was then performed using the Rj5-Rj10
primer combination, which specifically amplifies R. japonica.
Agarose electrophoresis detected the target size of 357 bp
as the amplified product. The nucleotide sequence of theamplified product was analyzed by direct sequencing. The
nucleotide sequence matched 100% with that of R. japonica(GenBank accession no. U83442). Serum IgG and IgM antibody titers were examined against R. japonica by indirect
immunofluorescence assay. The IgG and IgM titers were
1:320 and 1:80, respectively.
Tsutsugamushi disease and Japanese spotted fever are two
diseases caused by rickettsial infection in Japan (1). Within
Awaji Island, these diseases occur in different regions:tsutsugamushi disease in the northern part of the island andJapanese spotted fever in the southern Yuzuruha Mountainarea (4). This is probably due to the different distributionof the respective vectors. There have been several cases ofeither disease annually. It is very difficult to differentiate thesetwo diseases based on clinical symptoms, but they can be
epidemiologically differentiated to some degree based on thetime of year and the geographical location in which theyoccur. The patient in this study presented all 3 of the major
signs for rickettsial infection, eschar, rash, and fever. The
patient was clinically suspected to have Japanese spotted
fever, according to the time and location of the incidence.
Therefore, minocycline administration was started promptly,
and the patient’s conditions temporarily improved. However,the patient died from hemorrhaging manifestation.
The case fatality ratio of rickettsiosis by the spotted fevergroup is low. Rocky Mountain spotted fever has an exceptionally high case fatality rate of 3.7% (6). Kodama et al. (7)reported the first fatal case of Japanese spotted fever in 2001
in Awaji Island, but they did not confirm Rickettsia infection
serologically. The patient in the present report was an elderlyperson. Although diabetes mellitus was not observed in his
medical history, diabetes was thought to be the underlying
disease according to the elevated blood sugar level and a highlevel of HbA1c. Therefore, it is likely that the patient was in
an immunocompromised state, and this condition was one of
the factors which contributed to the fatal outcome. For those
who are old and predicted to have poor prognosis, steroid
therapy has been reported to be effective, and the use of an
antibacterial agent of the new quinolone group should beconsidered in combination with minocycline from the startof the treatment (1).
There is no gender difference in the reported cases of Japanese spotted fever. People of all age groups can be affected,
but two-thirds of the patients are 50 years old or older. This isprobably due to the strong social activity of the elderly people
in the mountain village, rather than disease sensitivity. In
recent years, the numbers of Japanese spotted fever cases havebeen increasing (8). Considering the increase in the percentage of the elderly population in semi-mountainous areasin Japan, it is likely that severe and fatal cases of Japanesespotted fever will increase in the future. On the other hand,
healthcare providers are not provided enough information
regarding this disease. Further, specific serodiagnostic tests
and PCR are not widely used. Therefore, it is important tofacilitate the use of these diagnostic techniques, and to provide
the general residents with sufficient information concerning
this disease.

Fig. 1. Location of Yuzuruha Mountain area in Awaji Island.

hospital. At the first visit, other general findings included aheight 160 cm, weight 50 kg, body temperature 36.4°C, bloodpressure 102/58 mm Hg, pulse rate 86/min and regular, andSpO2 97%. There were no abnormal findings in the chestregion, and neither abdominal mass nor hepatosplenomegaly
was palpable. Lymph node swelling was not found. No neurological abnormality was observed. Diffuse erythema of 7 mm
in diameter was present on each bilateral lower thigh, and abite mark (eschar) of a tick was evident on his anterior rightshoulder.
Laboratory data were as follows: red blood cell count 4.48
× 106/μl, Hb 13.8 g/dl, Ht 39.1%, white blood cell count
12,500/μl, platelet count 52,000/μl -- thrombocytopenia observed, FDP 54 μg/ml, suggesting concurrent DIC. Mild
hepatopathy and dehydration and a marked elevation of CRP
at 20.34 mg/dl were observed. Weil-Felix reaction was negative: OX19<1:80, OX2<1:20, and OXK<1:20. Blood sugar
level was elevated at 462 mg/dl and HbA1c 6.7%. As anunderlying disease, concurrent diabetes was suspected basedon the high blood sugar level. Findings from diagnostic imaging were noncontributory.
Because of the presence of an eschar and rash, it was suspected that liver dysfunction and DIC were due to rickettsial
infection. Minocycline 200 mg/day, heparin 10,000 units/day, and fluid replacement for dehydration were started
for treatment. On day 7, the 2nd day of hospitalization, CRP
decreased to 17.7 mg/dl. Physical findings of inflammation
started to improve and liver enzyme levels started to normalize. On day 8, blood pressure was 84/48 mm Hg, showing a
rapid decline. Thereafter, the patient had repeated bloody stool
mixed with red blood clots, and purpura appeared over theentire body. The patient eventually had cardiac arrest and death
was confirmed on the same day. The autopsy demonstrated
bilateral pleural effusion and oozing hemorrhage from themucous membranes of the stomach to the large intestine.
DNA was extracted from the blood in EDTA collected atthe initial examination. PCR (5) was performed with the R1-This article appeared in the Infectious Agents Surveillance242

5. Furuya, Y., Katayama, T., Yoshida, Y., et al. (1995): Specific amplification of Rickettsia japonica DNA from clinical specimens by PCR. J.
Clin. Microbiol., 33, 487-489.
6. Treadwell, T.A., Holman, R.C., Clarke, M.J., et al. (2000): Rocky Mountain spotted fever in the United States, 1993 - 1996. Am. J. Trop. Med.
Hyg., 63, 21-26.
7. Kodama, K., Senba, T., Yamauchi, H., et al. (2002): Fulminant Japanesespotted fever definitively diagnosed by the polymerase chain reaction
method. J. Infect. Chemother., 8, 266-268.
8. National Institute of Infectious Diseases and Tuberculosis and Infectious Diseases Control Division, Ministry of Health, Labour and Welfare(2006): Scrub typhus and Japanese spotted fever in Japan, as ofDecember 2005. Infect. Agents Surveillance Rep., 27, 27’-28’.

Report (IASR), vol. 27, p. 36-37, 2006 in Japanese.
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