[Emerging Infectious Diseases * Volume 3 * Number 2 * April-June 1997]
Synopses

Japanese Spotted Fever: Report of 31 Cases and Review of the Literature

Fumihiko Mahara
Mahara Hospital, Tokushima, Japan
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This article is also available in Japanese. The Japanese version can be
accessed at http://www.cdc.gov/ncidod/EID/eid.htm

      Spotted fever group (SFG) rickettsioses, which are transmitted
      by ticks, were long thought not to exist in Japan. Three
      clinical cases of Japanese spotted fever (JSF) were first
      reported in 1984. The causative agent was isolated and named
      Rickettsia japonica. Through October 1996, 31 cases were
      diagnosed as JSF in Tokushima Prefecture. Infected patients
      typically had acute high fever, headache, and characteristic
      exanthema; eschar was observed in 90%. After the discovery of
      JSF, more than a hundred cases were reported in southwestern
      and central Japan. Recent surveys show ticks to be the most
      probable vectors. As an emerging infectious disease, JSF is not
      commonly recognized by clinicians; therefore, even though it
      has not caused fatal cases, it merits careful monitoring.

The spotted fever group (SFG) rickettsioses, which are transmitted by
ticks, have a worldwide distribution. Japanese spotted fever (JSF) is one
of the newcomers of this group (1); the first clinical cases were reported
in 1984 (2). The causative agent was isolated and named Rickettsia japonica
(3). Because outbreaks were sporadic and limited, clinical reports
concerning JSF, especially from specialists in dermatology and physiology
and from general practitioners, were scarce. JSF was first found in
Tokushima Prefecture, on the island of Shikoku in southwestern Japan;
Tsutsugamushi disease, an important rickettsiosis in Japan, was found there
soon afterwards (4). Through October 1996, 31 clinical cases of JSF and 11
cases of Tsutsugamushi disease were diagnosed at Mahara Hospital, Tokushima
Prefecture. During the same period, 45 cases of human tick bites were
recorded in this JSF-endemic area in the same hospital. This article
describes JSF's history, clinical characteristics, and differences from
Tsutsugamushi disease and summarizes current information about the
epidemiology, vectors, and causative agent of JSF.

History

In the 1980s, clinicians believed that Tsutsugamushi disease (scrub typhus)
was the only rickettsial disease in Japan except for sporadic outbreaks of
epidemic typhus in the 1950s. In Tokushima Prefecture, neither disease has
been reported in the last two decades. In May 1984, a 63-year-old woman
(the wife of a farmer) was hospitalized at Mahara Hospital with high fever
and erythematous nonpruritic skin eruptions over the entire body.
Antibiotics (-lactam and aminoglycoside) used for common febrile
infections were not effective, but the patient gradually became afebrile in
2 weeks without effective treatment. In May and July 1984, two additional
patients with similar symptoms were treated at the same hospital.
Doxycycline was markedly effective in these cases. Before the onset of
illness, the patients had collected shoots from bamboo plantations on the
same mountain. In two of the patients, an eschar was observed.
Tsutsugamushi disease was suspected. However, results of Weil-Felix tests
showed positive OX2 serum agglutinins, and OXK were negative in all three
cases. These results did not indicate Tsutsugamushi disease, but rather
OX2-positive infections, i.e., SFG rickettsioses (1).

The cases were subsequently confirmed by complement fixation test with
antigens of SFG rickettsiae (5,6). The name Japanese spotted fever was
proposed for these infections (7) and has been commonly used since then
(8-10). Oriental spotted fever (11) is a synonym for JSF. The causative
agent was isolated in 1986 (12) and named R. japonica (3).

Clinical Features

The clinical features of the 31 patients whose illness was diagnosed as JSF
at Mahara Hospital from 1984 to October 1996 were analyzed. The disease
developed abruptly, with the common symptoms of headache (25 [80%] of 31
patients), fever (31 [100%] of patients), and shaking chills (27 [87%]).
Other major objective symptoms of JSF included skin eruptions (31 [100%])
and tick bite eschars (28 [90%]). Most patients (28 [90%]) complained of
malaise; joint and muscle pain or numbness of the extremities was rarely
mentioned. In the acute stage, remittent fever accompanied by shaking
chills was frequently observed. In severe cases, high fever (40C or more)
continued for several days (Figure 1). The maximum body temperature was
38.5C to 40.8C (mean 39.5C), which was higher than that seen in patients
with Tsutsugamushi disease (38.5C ~ 39.1C). With abrupt high fever or, a
few days after onset, fever of unknown origin, the characteristic erythemas
developed on the extremities and spread rapidly (in a few hours) to all
parts of the body including palms and soles, without accompanying pain or
itching. These eruptions were the size of a grain of rice or soybean, and
the margin of each of the spots was unclear (Figure 2). The erythemas
became remarkable during the febrile period and tended to spread more over
the extremities than the trunk. Palmar erythema, a characteristic finding
not seen in Tsutsugamushi disease, disappeared in the early stage of the
disease. The erythemas became petechial after 3 to 4 days, peaked in a week
or 10 days, and disappeared in 2 weeks. However, in severe petechial cases,
the brown pigmentation remained for 2 months or more. Eschar was observed
on the hands, feet, neck, trunk, and shoulders of patients (Figure 3). This
eschar generally remained for 1 to 2 weeks, but in some cases it
disappeared in a few days. Eschars in JSF patients are smaller than those
seen in patients with Tsutsugamushi disease and may be missed without
careful observation. Regional or generalized lymphadenopathy, which is
observed in almost all cases of Tsutsugamushi disease, was not remarkable
in JSF patients. Swelling of the liver and spleen was observed in a few
patients. One patient had cardiomegaly (5), and in another area, a patient
had central nervous system involvement (13).

[Figure 1] [Figures not available in ASCII version]
Figure 1. Fever and clinical course, 62-year-old woman.

   [Figure 2] [Figures not available in ASCII version]
   Figure 2. Skin eruptions, hospital day 3.

[Figure 3] [Figures not available in ASCII version]
Figure 3. Small and shallow eschar on admission, which disappeared in a
few days.

Laboratory Examinations

The results of laboratory examinations of JSF patients are almost the same
as those of patients with common SFG rickettsioses. During clinical
examinations at the initial stage of the disease, urinalyses registered a
slight positive reading for protein and occult blood, which may lead to a
misdiagnosis of urinary infection. In the acute stage, leukocytosis may
also be found with leukopenia (3,600~12,800), and a left shift in leukocyte
count was observed. Thrombocytopenia (6.8~35.3) may also be found. In week
1 to 2, leukocyte counts increased slightly, and lymphocyte counts tended
to increase. Among biochemical examinations, C-reactive proteins were
strongly positive, and liver functions were slightly impaired but returned
to normal in 2 to 3 weeks.

Serologic Results

Serodiagnosis for JSF is usually performed by the indirect immunoperoxidase
(IP) or immunofluorescence (IF) techniques, with antigens prepared from R.
japonica or other SFG rickettsiae. With the IP test, IgG and IgM antibodies
were detected in the sera beginning on day 9 after the onset of fever;
titers of IgG antibodies were higher than those of IgM antibodies (14). The
IF test had similar results (15). In the 31 clinically diagnosed cases of
JSF in Tokushima Prefecture at Mahara Hospital, all patients had
significant changes in serum IP antibody titers to R. japonica, and 27
(87%) had significant changes in OX2 agglutinin titers by the Weil-Felix
technique (10,14; F. Mahara, unpub. data).

Treatment

Antibiotics such as penicillins, -lactams, or aminoglycosides, commonly
used in the empiric treatment of febrile disease, were completely
ineffective, but doxycycline and minocycline were markedly effective in
treating the JSF patients (16).

On the first day of hospitalization in one patient with severe disease
(Figure 1), fever of more than 40C with shaking chills persisted after the
antibiotics cefazolin and fosfomycin were administered. The general
condition of the patient worsened and on the morning of the third day,
generalized edema and confusion developed. On day 3, the patient was given
drip infusion of doxycycline 300 mg per day, which was dramatically
effective; the fever decreased to 38C during the first drip infusion.

In an in vitro study, minocycline was the most effective antibiotic against
R. japonica, followed by other tetracycline antibiotics (17,18). In
contrast, the sensitivity to -lactam and penicillin was lower or
negligible, but quinolones were effective against the JSF agent (18). Three
patients were treated with a new quinolone (tosufloxacin 300 mg per day in
three divided doses per os), which proved effective in two cases (9).
Patients with dehydration received drip infusion of doxycycline or
minocycline (200 mg to 300 mg per day for 3 to 7 days), and after becoming
afebrile, received 200 mg per day 2 divided doses to prevent relapse.
Patients suspected of having JSF should receive empiric therapy with
minocycline or doxycycline without waiting for serologic confirmation of
illness.

Epidemiology

From 1984 to 1995, 144 cases of JSF were reported by the National
Institutes of Health in Japan (19; Figure 4). Case reports included only
the number of cases and prefectures where cases were reported, including
Tokushima Prefecture. According to this information, JSF-endemic
prefectures are located along the coast of southwestern and central Japan
in a warm climate (Figure 5). The landscape is diverse, including bamboo
plantations, crop fields, coastal hills, and forests (20). Of the 31 JSF
patients in Tokushima Prefecture, nine were male, and 22 were female. Ages
were 4 to 78 years, but most patients (68%) were 60 to 70 years old. The
onset of the disease was 2 to 8 days after work in the fields. In this
prefecture, farmers work in the forest to gather bamboo shoots in the
spring and chestnuts in the autumn; cases occurred from April to October
(6,18; Figure 6). In this area, we can distinguish seasonal differences in
the occurrence of JSF and Tsutsugamushi disease; whereas JSF occurs from
spring to autumn, Tsutsugamushi disease occurs in winter
(November-February). Although seasonal differences occur in the western
parts of Japan, the prevalent seasons for Tsutsugamushi disease vary in
other parts of Japan (21).

          [Figure 4] [Figures not available in ASCII version]
          Figure 4. The number of Japanese spotted fever patients
          in Japan (1984-1995).

              [Figure 5] [Figures not available in ASCII version]
              Figure 5. Geographic distributions of JSF and
              Tsutsugamushi disease in Japan.
             [Figure 6] [Figures not available in ASCII version]
             Figure 6. Seasonal prevalence of Japanese spotted
             fever and Tsutsugamushi disease.

Like other SFG rickettsioses, JSF is presumed to be transmitted by a tick
bite. The high proportion of patients with tick bite eschars supports this
hypothesis. Thirteen JSF patients (28.9%) recalled tick bites before the
onset of illness; however, the ticks had been lost, and no specimens from
the patients were available for further study. From 1984 to October 1996,
45 persons with tick bites were recorded at Mahara Hospital (Table 1).
Identified ticks included three genera and eight species.

      Table 1. Cases of human tick bites, Mahara Hospital, 1984-1996
      ---------------------------------------------------------------
                                    Female Male  Nymph Larva Total
      ---------------------------------------------------------------
      Haemaphysalis flava           1            4           5
      Haemaphysalis longicornis     8      1     3     2     14
      Amblyomma testdunarium        4      1     12          17
      Ixodes ovatus                 1                        1
      Ixodes nipponensis            4                        4
      Ixodes persulcatus                         2           2
      Ixodes tanuki                 1                        1
      Haemaphysalis kitaokai        1                        1
      Totals                        20     2     21    2     45
      ---------------------------------------------------------------

Three genera and six species of ticks have been reported as positive for R.
japonica in JSF-endemic areas (Table 2). Hemolymph samples from Dermacentor
taiwanensis, Haemaphysalis flava, Haemaphysalis formosensis, Haemaphysalis
hystricis, Haemaphysalis longicornis, and Ixodes ovatus were positive when
tested by the IP technique using a species-specific monoclonal antibody
against R. japonica (22). R. japonica was also detected by IF in the
hemolymph of H. longicornis (23). A polymerase chain reaction (PCR)
technique using species-specific primers detected R. japonica in H.
hystricis (24), H. flava, and I. ovatus (25). The agent has also been
detected in H. longicornis by restriction fragment length polymorphism of
PCR product (23). Of these, H. flava, H. longicornis, and I. ovatus
commonly feed on humans in Japan (26). Recent tick surveys in Japan have
identified two serotypes or species of SFG rickettsial isolates other than
R. japonica, which are of uncertain clinical significance (27,28).

Table 2. Reported tick species positive for Rickettsia japonica and their
prevalence in endemic disease areas
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                                     No. positive/no. examined
                           ------------------------------------------------
       Tick species           Tokushima          Kochi        Kanagawa
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Dermacentor taiwanensis    3/5(a), 1/1(b)   -               -
Haemaphysalis flava        6/36(a)          3/10(a)         1-3/90(c)
Haemaphysalis formosensis  -                10/16(a)        -
Haemaphysalis hystricis    +(d)             5/9(a)          -
Haemaphysalis longicornis  -                1/1(a), 6/9(e), -
                           5-33/33(f)
Ixodes ovatus              1/13(a)          -               1/16(c)
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(a)Hemolymph test by immunoperoxidase stain using R. japonica-specific
monoclonal antibody (22).
(b)Isolation (28).
(c)Polymerase chain reaction (PCR) using the primers designed for
amplifying the genomic DNA from only R. japonica (25).
(d)PCR method same as the above (24). Number was not shown.
(e)Hemolymph test by immunoflurescein stain using R. japonica-specific
monoclonal antibody (23).
(f)Restriction fragment length polymorphism of PCR product (23).

Pathogen

The etiologic agent was first isolated from a patient (in Kochi Prefecture)
in 1986 (12). In 1987, the causative rickettsia was also isolated from a
JSF patient in Tokushima Prefecture (29-31). The former isolate is the type
strain YH (ATCC VR-1363), later named R. japonica, a new SFG rickettsia;
the latter strain (Katayama) was the first isolate from JSF-endemic areas
outside Kochi (3,32). The Katayama strain type and R. japonica were
demonstrated by serologic analysis using monoclonal antibodies (33).
Serotyping by use of the reciprocal crossreactions of mouse antisera to six
human isolates from Tokushima and the type strain YH or R. japonica also
indicated that these are the same species (34). In 1988, another strain was
isolated from a patient in Awaji Island, Hyogo Prefecture, which is
considered a new area of JSF-endemic disease (35).

Recently, an isolate from a febrile patient in Wakayama Prefecture was also
reported as R. japonica (36). In an electron microscopy study, R. japonica
were generally recognized as short rods or pleomorphic coccobacillary forms
less than 2 mm in length and 0.5 mm in diameter and could be found not only
in the cytoplasms but also in the nuclei of the host cells (37). A
multilayered mesosome-like structure was observed in the rickettsiae
multiplying in a host cell (38). This unique structure has not been
reported in other species except in Rickettsia prowazekii (39). After the
initial isolation, at least 20 rickettsial strains have been isolated from
JSF patients by cell culture techniques or nude mouse passage in Tokushima,
Kochi, Hyogo, Chiba, and Wakayama Prefectures. However, it has not been
determined if their strains differ in virulence.

Ten diseases caused by SFG rickettsiae have been reported in humans (40):
Rocky Mountain spotted fever, Mediterranean spotted fever, Siberian tick
typhus, African tick bite fever, Queensland tick typhus, Japanese spotted
fever, Israeli spotted fever, Astrakhan spotted fever, Flinders Island
spotted fever, and rickettsialpox. The clinical symptoms of JSFa triad of
high fever, skin eruptions, and tick bite escharare similar to those of
typical SFG rickettsioses. With regard to skin eruptions, eschar, and
severity of the disease, JSF is more akin to Mediterranean spotted fever
and Siberian tick typhus than to Rocky Mountain spotted fever. Recent tick
surveys indicated that the most probable vectors of JSF are H. flava, H.
longicornis, and I. ovatus.

In Japan, the clinical features of JSF are similar to those of
Tsutsugamushi disease; however, close clinical observation exposes the
differences between the two diseases. Widespread outbreaks of Tsutsugamushi
disease have been reported repeatedly in recent years (21). No fatal cases
of JSF have been reported. However, death rates from other SFG
rickettsioses (approximately 2.5% for Mediterranean spotted fever [41] and
3% to 7% from Rocky Mountain spotted fever [42]) suggest that unless JSF is
treated appropriately, it can pose the same risk. If JSF is suspected,
empiric treatment should begin without delay during the early stages of
disease.

Acknowledgments

The author thanks Professor Emeritus Suto T., Department of Microbiology,
Akita University, for serologic confirmation; Professor Jan Kazar, Slovak
Academy of Sciences, for his helpful advice; Drs. Fujita H., Ohara Research
Laboratory and Takada N., Fukui Medical School, for epidemiologic studies;
and all colleagues who collaborated in the investigations.

Dr. Mahara is chief director of Mahara Hospital, Tokushima, Japan. He
serves as a counselor of the Japanese Association for Infectious Diseases
and is a member of the International Eurasian Academy of Sciences.

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Emerging Infectious Diseases
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Atlanta, GA

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