Download Spotted Fever Group Rickettsial Infections in Australia

876
Spotted Fever Group Rickettsial Infections in Australia
Daniel J. Sexton, Brian Dwyer, Richard Kemp,
and Stephen Graves
From the Division of Infectious Diseases, Duke University Medical
Center, Durham, North Carolina; Fairfield Infectious Diseases Hospital,
Fairfield, Victoria, Australia; and the Infectious Diseases Unit, Royal
Brisbane Hospital, Brisbane, Queensland, Australia
In 1946 Andrew et al. [1] described a new tick-borne disease in Australian soldiers on wartime training exercises in
the bush of northern Queensland. A rickettsial organism was
isolated from two of 12 infected soldiers, and the illness was
designated North Queensland tick typhus. Plotz et al. [2] performed cross-protection and serologic tests in guinea pigs,
using an isolate (PHS) from one of the cases studied by Andrew and colleagues. They concluded that the isolate was a
new spotted fever group (SFG) organism. In 1950 Philip [3]
named the organism Rickettsia australis.
Subsequently, this infection was recognized throughout
coastal Queensland, and the name Queensland tick typhus
(QTT) became widely used even though cases were also described in the northern and central coastal regions of New
South Wales. QTT was accepted as a distinct clinical entity
and included in standard textbooks, but only 21 cases were
reported in the literature from 1946 to 1989 [1, 4-9].
In 1990 Stewart, Graves, and associates [10, 11] observed
26 cases of a spotted fever-like illness in residents of Flinders
Island, Tasmania. Shortly thereafter, a similar illness was
reported in seven patients from Gippsland in eastern Victoria
[12] and the first fatal case of QTT was recognized [13].
This paper summarizes the information on 62 Australian
cases ofSFG rickettsial infection, including 16 previously unreported cases from Victoria, Queensland, and New Soath
Wales. For the purpose of this review, we are assuming that
Received 20 September 1990; revised 13 December 1990.
Reprintsand correspondence: Dr. Daniel 1. Sexton, Box 3605, Duke University Medical Center, Durham, North Carolina 27710.
Reviews of Infectious Diseases 1991;13:876-86
© 1991 by The University of Chicago. All rights reserved.
0162--088619111305-0036$02.00
the cases from Flinders Island and Victoria [10-12] are due
to R. australis, even though an etiologic agent has not yet been
isolated. We review the epidemiology, ecology, and laboratory and clinical features of R. australis and discuss unresolved
issues concerning SFG rickettsial infections in Australia.
Incidence, Definitions, and Methods
QTT, although a notifiable disease in Australia, is seldom
reported. Furthermore, the Australian Commonwealth Department of Health does not separate the three forms of typhus (murine, scrub, and tick) in its annual reports. From
1966 through 1985, 102 cases of typhus (all forms) were
reported in Australia. Seventy-three (72 %) of these 102 cases
were from Queensland. That 51 (50%) of the cases were
reported between 1982 and 1985 suggested either an increase
in incidence or improved reporting.
Data on the frequency of the three forms of typhus in
Queensland are available in the annual reports of the Department of Health and Medical Services of Queensland for 1966
through 1985. Of the 73 reported typhus cases, 12 (16%) were
tick typhus, 55 (75 %) were scrub typhus, and the remainder
were murine typhus or of unspecified type. Before 1985 the
Queensland health department required that all officially
reported cases of tick typhus be confirmed with specific antibodies to Rickettsia, but appropriate antigens either were not
available or were of doubtful validity (N. Stallman, personal
communication). Thus it is likely that QTT and other rickettsial diseases are underrecognized and/or underreported in Australia.
In the present study, clinical and epidemiologic data were
obtained from the literature (for 21 cases described from 1946
to 1980 [1, 4-9] and for a fatal case reported by our group
in 1990 [13]); from original clinical records (for the cases
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More than four decades ago, Rickettsia australis was discovered to be the etiologic agent of
Queensland tick typhus (QIT), yet many unanswered questions persist about the ecology,epidemiology, and clinical features of this disease. We review 46 previously published cases ofQIT along
with 16 cases discovered by active surveillance. QIT is usually a mild disease. Patients often
have regional lymphadenopathy and eschars. Some have vesicular rashes. Because clinical features overlap, serologic tests are necessary to distinguish QIT from other endemic Australian
rickettsial diseases (scrub and murine typhus). Only two tick vectors of R. australis have been
identified: Ixodes holocyclus and Ixodes tasmani. Until rickettsiae are isolated from patients in
Victoria and Tasmania, it remains unproven that spotted fever group infections in these locations
are due to R. australis. However, available serologic, epidemiologic, and clinical data suggest
that QIT is not confined to the area in which R. australis was first isolated (Queensland); rather,
it occurs along a 3,200-km span of eastern coastal Australia, from tropical to temperate climates.
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Rickettsial Infections in Australia
Results
Clinical Features
Sixty-two cases were identified. Their onset was usually
abrupt, although malaise, headache, a localskinlesion, and/or
tender lymphadenopathy occurred prodromallyin a few cases.
Most patients had headache and myalgia.
Skin rash began as early as I day and as late as 12 days
10
~-------------------,
8
C
A
S
E
S
I
6
:1_11
234
5
6
7
8
9
10
11
12
DAYS
_
Vic to ria / FI
~ NSW/Qld
Figure 1. Interval from onset of illness to skin rash in 62 cases
ofQfT.
after the onset of symptoms (figure 1). This interval averaged
4.4 daysin cases from New South Walesand Queenslandand
5.0daysin those from Victoria and Flinders Island. Only two
patientslacked a skin rash; one had a fourfoldincreasein titer
of antibodyto Proteus OX19 and an eschar [7], while the other
had an eschar at the site of a tick bite, a fourfold increase
in titers of antibodies to Proteus OX19and OX2, and detectable convalescent-phase CF antibody [1]. In the remaining60
patients, the rash was macular or maculopapular, evolving
to petechial in nine instances. In some cases the rash was
blotchy and sparse; in others it was generalized, including
the palms and soles. Six patients (10%) had a vesicular rash
that in several cases resembled chickenpox [1, 4, 5].
Eschars were described in 31 (50%) of 62 cases (table 1).
Only 28% of cases from Flinders Island and Victoria vs. 65%
Table 1. Epidemiologic and clinical characteristics of 62 cases of QTT, 1946-1989.
Value for cases with indicated geographic source
Feature: mode of data expression
Age" : mean (range) in y
Gender: no. male/no. female
Eschar": no.ltotal no. (%)
Lymphadenopathy": no.ltotal no. (%)
WBCs
Mean no. (rangej/mm''
Percentage with <5,OOO/mm3
Tick bite history'l: no.ltofal no. (%)
Hospitalization: no.ltotal no. (%)
Fourfold increase in CF or MIF titer:
no.ltotal no. (%)
Interval from tick bite to onset: mean
no. of days
Interval from symptom onset to rash
onset: mean no. of days
Flinders IslandlVictoria
36.1 (0.75-58)
14/11
7/25 (28)
13/25 (52)
5,887 (3,200-11,300)
37
8/25 (32)
9/25 (36)
14/24 (56)
New South Wales/Queensland
30.3 (3-75)
27/10
24/37 (65)
31/37 (84)
5,547 (2,400-11,000)
44
28/37 (76)
22/39 (59)
9/37 (24)
Total
32.2 (0.75-75)
41/21
31/62 (50)
44/62 (71)
5,692 (2,400-11,300)
41
36/62 (58)
31/62 (50)
23/62 (37)
5.0
5.7
5.5
5.1
4.4
4.6
NOTE. For the purpose of this comparison, the disease in Tasmania (Flinders Island) and Victoria is assumed to be QTT. although this etiology has not yet been proven.
• For Flinders Island/Victoria, n = 25; for New South Wales. Queensland, n = 37.
t Fisher's exact test, P < .01.
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reported by Stewart [10], Graveset aI. [11], and Dwyer et al.
[12]); and from a telephone survey of selected clinicians in
coastal Queensland, New South Wales, and Flinders Island,
Tasmania. Cases were also sought from the records of the
healthdepartmentsof Queensland and New South Wales, private and public clinical laboratories in Queensland and New
South Wales, and hospitals in Brisbane, Sydney, and Melbourne.
A case was included if R. australis was isolated (3 cases)
or if there was a clinical illness compatiblewith the diagnosis
and associated with any of the following: (1) a single
convalescent-phase titer of antibody to Proteus OXI9 or OX2
of ~I:I60 (9 cases) or a fourfold increase in titer (35 cases);
(2) a convalescent-phasetiter of CF antibody to R. australis
of ~1 :8 (9 cases) or a fourfold increase in titer (2 cases); or
(3) a single convalescent-phase titer of microimmunofluorescence (MIF) antibody to R. australis antigen of ~1:128 (17
cases) or a fourfold increase in titer (21 cases). Twenty-nine
(47%) of the 62 cases satisfiedtwoor more serologic criteria.
As cases from Flinders Island were collected retrospectively
in 1973-1987 and prospectively thereafter, nineof the 26 cases
reported by Stewart [10] did not meet our definition and thus
were excluded from this review.
877
Sexton et al.
878
Table 2. Epidemiologic and clinical characteristics of cases ..of
QTT with fourfold increases in titers of MIF or CF antibody.
No. of cases with featureltotal no.
(% with feature)
Clinical feature
Eschar
Lymphadenopathy
Tick bite*
* Fisher's exact test, P
< .0].
Flinders Island/
Victoria
New South Wales/
Queensland
7/14 (50)
8/14 (57)
4/14 (29)
5/9 (56)
7/9 (78)
9/10 (90)
Fifty percent of patients were hospitalized. The average duration of hospitalization was 6.0 days (range, 2-13 days). One
case ended fatally; the remaining patients recovered without
sequelae. The patient who died developed fever, rash, and
headache after a tick bite. Generalized seizures, pneumonia,
and renal and hepatic failure ensued, with death 14 days after
onset. Analysis of paired sera demonstrated a striking rise
in titers of MIF antibody [13].
Data on the duration of fever and rash were unavailable for
most patients. Andrew et al. [1] reported that fever lasted an
average of 7.5 days (range, 2-12 days) in their series of 12
patients. Stewart noted a duration of fever averaging 11 days
(range, 7-16 days) among eight hospitalized patients [10]. If
untreated, some patients had fever lasting as long as 2 weeks.
White blood cell (WBC) counts were available for 44 patients (table 1); 41 % of these patients had leukopenia (range,
2,400-4,900 X lQ6 WBCs/L), 56% had normal counts, and
only 3 % had leukocytosis. Platelet counts were measured in
less than half the group. Seven patients had counts of <150,000
X lQ6/L; five of these seven had counts of <100,000 X
106/L.
Minor abnormalities in hepatic function were seen in three
cases, and minor aberrations in renal function were detected
in one instance. However, tests of hepatic and renal function
usually were not done. Except for the fatal case, severe organ
dysfunction similar to that seen in Rocky Mountain spotted
fever and scrub typhus was not encountered.
Epidemiologic Features
Patients ranged in age from 9 months to 75 years. Only
nine cases (15%) occurred in people <20 years of age (figure
2). The male-to-female ratio was 2: 1 (table 1). Fifty-eight percent of patients had a history of tick bite; an additional 6 %
had a history of "insect bite" of doubtful or unknown type.
A higher percentage of cases from Queensland and New South
Wales involved a definite history of tick bite (tables 1 and 2).
However, in four cases from Flinders Island and Victoria, there
was a history of local "bite" marks of unknown cause. If these
cases are included among those associated with tick bites, the
difference between the two groups is less striking.
Nineteen (49 %) of 39 patients on whose occupation information was available may have acquired the infection secondary to their work or hobbies (e.g., beekeeping, bird watching,
farming, veterinary medicine, forestry work, military training). Fourteen patients had acquired the infection while on
holiday, and four patients sought medical care upon their return from a trip to another state.
Information on month of onset was available in all 62 cases.
Although cases occurred in every month of the year (figure
3), 72 % of those from Victoria and Flinders Island occurred
during spring and summer (October to February), whereas
78% of those from New South Wales and Queensland had
their onset during winter and spring (June to November).
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of those from New South Wales and Queensland had eschars
(P < .01, Fisher's exact test). Biopsies of eschars were done
in three cases. In one case the histopathologic picture was
similar "to an eschar of scrub typhus" [1]; in the other two
vasculitis with a mononuclear cell infiltrate was seen. Eschars
occurred on the head and neck (10 cases), the trunk (nine
cases), the extremities (eight cases), and the penis (one case),
with unknown sites in two cases. In four cases local skin lesions without necrosis were found. These were variously described as papules, pimples, ''bruised areas;' or "bite marks."
In numerous cases the tick had been previously removed at
the site of the eschar.
Seventy-one percent of patients had lymphadenopathy (table 1). In most cases this phenomenon was localized, usually
to the region of the antecedent tick bite or the coexistent eschar. Lymphadenopathy was described more frequently among
patients from New South Wales and Queensland than among
those from Flinders Island and Victoria (84 % vs 52 %; P <
.01, Fisher's exact test).
The clinical features of the 14 cases of QfT from Flinders
Island and Victoria that included fourfold increases in antibody titer and suspected rickettsial infection at the onset of
care were compared with those of the nine similar cases from
New South Wales and Queensland. The incidences of eschar
and lymphadenopathy were found not to be statistically different in these two groups (table 2).
The frequency of other signs and symptoms could not be
accurately determined from this retrospective review. However, the diverse features mentioned in a minority of case
reports and clinical records included joint pain (nine cases),
splenomegaly (six), cough (six), conjunctivitis (five), sore
throat (five), nausea (five), abdominal pain (two), and photophobia (two).
One patient acquired QTT during her second trimester of
pregnancy. She recovered uneventfully and delivered a healthy
child. No postnatal tests for transplacental infection were done.
One patient developed a small pericardial effusion, two experienced confusion, one had transient visual hallucinations,
and one presented with generalized seizures.
Illness varied from mild to fatal. Only 18 (29 %) of 62 patients received tetracycline; none received chloramphenicol.
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Rickettsial Infections in Australia
RID 1991;13 (September-October)
20
r - - - - - - - - - --
2 0 - 29
30-39
- - - --
40- 49
50-59
-
-
6 0 -69
879
----,
70 -
AGE GROUPS
Vi ctor ia /F I
...
~ NSW/ Old
o
Figure 2. Ages of 62 patients with QfT.
• O!
17 cases on
IJ........... Flinders Island
D
14
Figure 4. Location of presumed acquisition of cases of QfT
(1946-1989) .
12
10
C
A
S
E
s
8
6
I
4
2
0
SPRING
WIN TER
_
Vic l oria / FI
_Id~
SUMMER
FALL
~ NSW /Old
Figure 3. Season of onset of 62 cases of QTT.
Cases from southeastern Australia were reported as early as
August and as late as April, whereas those from northeastern
and central coastal Australia were reported from February
to December. Cases occurred over a 3,200-km span from
northern coastal Queensland to Flinders Island and as far west
as Wilson's Promontory in Victoria (figure 4). Infections were
reported from both suburban and rural areas; eight infections
(13%) were presumably acquired in suburban Sydney or
Brisbane.
Information on the interval from tick bite to onset of symptoms was available in ~7 cases. In a pattern similar to-that
of Rocky Mountain spotted fever, illness began 1-11 days
(mean: 5.5 days) after the detection of the tick bite (table 1).
The intervals were simiiar in cases from New South Wales
and Queensland (mean, 5.7 days) and in cases from Flinders
Island and Victoria (mean, .5.0 days).
A clustering of cases was seen in one household [12]. Four
family members became ill after bush-walking on a holiday.
Although none had documented tick bites, all had eschars and
fourfold increases in antibody titer.
Serology
WeiI-Felix (WF) tests were done in 45 cases. WF titers increased by fourfold in 35 patients. An additional nine patients
had a single convalescent-phase titer to Proteus OX19 or OX2
of ;;l:1:160. Twenty-three (66%) of 35 patients with fourfold
increases in WF titers also had diagnostic MIF or CF titers .
One patient had a negative WF test with a positive MIF test.
In 43 (96 %) of 45 cases with WF antibody tests, the OXK
titer was ~1 : 80. Two patients had a solitary positive result
in an assay for OXK agglutinins; both of these individuals
had fourfold rises in titers of MIF or CF antibody.
Since murine typhus may also produce Proteus OX2 and/or
OXl9 agglutinins, the 44 cases with positive WF reactions
were analyzed separately. Twenty-eight (64 %) of the patients
had eschars, 27 (61%) had positive MIF or CF antibody tests
(with use of SFG antigens) , and 25 (57 %) had antecedent tick
bites. Only three cases failed to meet any of these criteria.
The Organism
Isolates of R. australis. To date, only six isolates of R.
australis have been reported: three from humans and three
from ticks [1, 14, 15]. By serendipity, Andrew et al. used
vitamin-deficient white mice to make their original rickettsial isolations [1] . Thereafter, the two strains isolated by this
group (FIK and PHS) were passaged and studied in guinea
pigs. Infected guinea pigs developed fever and a scrotal reaction but recovered. The third isolate of R. australis from a
human source, the JC (Cutlack) strain, was obtained from
a Brisbane teenager in 1955 [15] and was maintained thereafter in weaned mice. Initially, the JC strain produced only
mild splenomegaly in weaned mice and no reaction in guinea
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_
880
Sexton et al.
antibodies to the FIK isolate of R. australis; none had antibody to R. typhi antigens [23].
In 1948 Lackman and Parker [24] injected rabbits with
washed rickettsial suspensions. Serologic cross-reactions between R. australis and typhus group (TG) rickettsiae or Coxiella bumetii did not occur. Subsequently, Lackman and
Pickens [25] showed that all SFG rickettsiae, including R. australis, possess a soluble antigen that fixes complement in serum from guinea pigs convalescent from Rocky Mountain
spotted fever. Parker et al. [26] further demonstrated the
uniqueness of R. australis by showing that guinea pigs inoculated with live organisms of this species were not immune
to later challenge with Rickettsia rickettsii.
Laborious guinea pig cross-immunity tests using washed
and formalin-killed rickettsial suspensions demonstrated that
R. australis elicits CF antibodies that cross-react with R. akari
but not with other SFG rickettsiae. Thus R. akari and R. australis are both classified as belonging to spotted fever subgroup C [27, 28].
Mice immunized with R. australis develop unique CF antibodies that clearly distinguish this species from R. akari
and other pathogenic and nonpathogenic SFG rickettsiae [20].
R. australis reacts strongly with homologous antisera and
weakly with only two other SFG rickettsiae (Rickettsia montana and the Ixodes pacificus strain) in the MIF assay [29].
The significance of these cross-reactions is doubtful. Recently,
R. australis was compared with the Thai tick typhus agent
(TT-118) and a newly described Japanese SFG rickettsia species (Rickettsiajaponica); R. australis cross-reacted with neither species in the mouse MIF test. The western
immunoblotting patterns ofTT-118 and R. japonica were also
dissimilar to that of R. australis [30]. Experiments with
specific mouse antisera and SFG rickettsial antigens disclosed
that R. australis has a unique protein immunoblot pattern [31].
Thus, at present, R. australis appears to be a unique SFG
species.
The nature of the human immune response to R. australis
is largely unknown. Spleen cells from mice immunized with
R. conorii or R. akari proliferate in vitro when exposed to
R. australis, Rickettsia sibirica, or R. rickettsii [32]. This
finding suggests that a common SFG group antigen stimulates lymphocytes, whereas other R. conorii-immune cell lines
respond poorly to R. australis [33].
To our knowledge, the DNA base composition of R. australis has not been described. However, the DNA molar base
compositions of those SFG rickettsiae tested thus far (R. rickettsii, R. conorii, andR. sibirica) are remarkably similar [34].
DNA-DNA hybridization experiments comparing R. rickettsii with R. australis show 53 % DNA relatedness; this degree
of relatedness is less than that between R. rickettsii and R.
conorii (91%-94%), R. siberica (70%-74%), and R. montana (73 %) but greater than that between R. rickettsii and
R. akari (46 %) [21].
Comparative electrophoresis of SFG rickettsial proteins
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pigs, but successive passages resulted in detectable rickettsemia and clinical symptoms. This strain was presumed to be
identical to other strains of R. australis on the basis of crossreacting antibodies to Rickettsia akari; R. australis antigens
were not used in its initial evaluation.
In 1968 Campbell and Pope [16] demonstrated that newborn mice were more susceptible to the PHS strain of R. australis than were weaned mice, chick embryos, or guinea pigs.
Subsequently, newborn mice were used in the isolation of three
strains of SFG rickettsiae from naturally infected ticks (Ixodes holocyclus and Ixodes tasmani) in Queensland [14]. All
three isolates were presumed to be R. australis on the basis
of cross-protection tests in infected guinea pigs and the production of characteristic clinical symptoms in infected suckling
mice.
No isolations of R. australis from animals or ticks have been
reported since 1971. It is unknown whether strain-specific variations in virulence and PAGE patterns, similar to those seen
with Rickettsia conorii, occur with R. australis [17-19]. The
effect of more than 40 years of laboratory storage and .passage on the pathogenicity, immunogenicity, and molecular biology of the PHS strain is uncertain. However, the isolate still
produces fever, diarrhea, scrotal edema, and inflammation
in guinea pigs; remains lethal for newborn mice; and elicits
an immune response in adult mice and guinea pigs (authors'
unpublished observations). The three isolates of R. australis
from humans (FIK, PHS, and JC) have not been compared
with one another in order to verify that they are - as has been
assumed - identical. The significance of reported differences
among these isolates is unknown. For instance, the JC strain
was first isolated and serially passaged in weaned mice,
whereas Plotz et al. [2] were unable to isolate or passage the
PHS strain in their strain of laboratory mice. Unfortunately,
the FIK strain and the three strains of R. australis isolated
from ticks are no longer available for analysis (1. H. Pope,
personal communication). The JC or Cutlack strain (also
called W58) still exists in several laboratories [20, 21].
Laboratory and serologic studies. The PHS strain of R.
australis, isolated in 1944 by Andrew et al. [l] and designated by an infected soldier's initials, has also been called the
Phillips strain by some American investigators [22]. This
strain has been the basis of most published laboratory and
serologic studies.
In 1946 Funder and Jackson [23] and Plotz et al. [2] simultaneously demonstrated that R. australis, unlike Rickettsia
typhi, grew in both the cytoplasm and the nuclei of tissue culture cells. Both groups of researchers did guinea pig crossimmunity tests and found confusing cross-resistance with
Rickettsia prowazekii, R. typhi, and R. conorii. However, immunity to heterologous strains gradually disappeared, while
that to the homologous strain wasdurable. Infection in animals
produced immunity to rechallenge with the same agent and
elicited strain-specific CF antibodies. In addition, the original patients described by Andrew et al. [1] had specific CF
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Rickettsial Infections in Australia
Ecology
The evolution of the varied SFG rickettsiae is not understood. Marchette speculated that R. australis either evolved
from R. akari organisms that reached Australia with the movement of murids from Southeast Asia or evolved independently
from symbiotes in indigenous ticks that fed on the early Australian reptilian or marsupial fauna [43]. Neither theory has
yet been tested by modem methods of molecular biology [44].
Limited data are available on the life cycle of SFG rickettsiae in Australia. The extent and frequency of natural infection with R. australis, the bionomics of its vertebrate hosts,
the species and stages of ticks that naturally attack host
animals, and the dynamic interaction of vertebrate host, tick,
and R. australis have been incompletely studied. Data on the
duration 'of rickettsemia in nonimmune animals, the ability
of experimentally infected animals to infect vector ticks, transovarial or transstadial transmission in ticks, and the appearance arid persistence of antibodies - all necessary to elucidate
the ecology of R. australis - are lacking.
Shortly after the description of QTT by Andrew et a1. [1],
Fenner [45] showed that eight of 111 animals trapped near
the site of Andrew's original cases had CF antibodies to the
FIK strain of R. australis. Cook and Campbell [46] subsequently confirmed this finding by detecting CF antibody
in 54 of 307 bandicoots and rodents trapped in northern
Queensland.
More than 500 specimens from more than 15 species of
wild animals in Australia havebeen inoculated into experimental hosts, yet no isolations of R. australis have been made.
These results are in striking contrast to successful attempts
to isolate Rickettsia tsutsugamushi and C. burnetii from similar
animals [47-51]. Indeed, it is surprising thatR. australis was
not accidentally discovered in the numerous studies of scrub
typhus and Q fever done in northern Australia during the past
40 years, since the techniques used to find C. bumetii, R.
typhi, and R. tsutsugamushi theoretically would result in recovery of R. australis as well [51-60].
Even before it was proven to carry R. australis, I. holocyclus was considered a vector of QTT as it had been detected
on humans with the disease [1, 4] and was known to be the
principal human-biting tick in Queensland and New South
Wales [61]. Found only in Australia, I. holocyclus feeds on
a wide array of domestic and wild animals, including some
previously shown to have CF antibodies to R. australis [45].
In fact, this tick species is an indiscriminate feeder, attacking
almost any bird or mammal that comes its way; it may have
a predisposition for bandicoots. I. holocyclus is a well-known
cause of tick paralysis in humans, dogs, bandicoots, and even
kangaroos [62-64].
The distribution of I. holocyclus is chiefly coastal; however, in tropical Queensland this species is also prevalent in
rain forests [65, 66]. Its range extends south to the Bairnsdale district in eastern Victoria, but its western limit is uncertain. Although transient importation cannot be excluded,
canine tick paralysis due to I. holocyclus has been reported
in Melbourne, and there have been unconfirmed reports of
sightings in Western Australia [67, 68].
Adult ticks of this species can be found throughout the four
seasons but are most numerous from August to December.
Nymphs are active chiefly through winter and early spring,
larvae mainly in summer and autumn [69].
I. tasmani is the most common and widespread of the Australian species of Ixodes. Campbell and Domrow [14] found
R. australis in one lot of three I. tasmani ticks removed from
a rat but discounted its importance as a vector affecting humans as it rarely bites humans in northern Australia. However, the latter authors suggested that I. tasmani might play
a role in the maintenance of R. australis in small animals [14].
Perhaps I. tasmani is a vector in Tasmania since it is the most
abundant tick species in this region and is known to bite humans on Flinders Island [10]. Found in eastern Australia from
Queensland to Tasmania, I. tasmani has been detected on 58
species of wild animals, on humans, and on dogs and other
domestic animals. Unlike I. holocyclus, I. tasmani is not
confined to coastal regions but exists in interior parts of South
and Western Australia [68].
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demonstrates that R. australis, R. rickettsii, R. conorii, and
Rickettsia parkeri have six polypeptide bands of similar mobilities, one of which is absent from R. akari [35]. SFG rickettsiae appear to have species-specific and group-reactive
protein epitopes. Monoclonal antibodies specific for protein
antigens of R. akari, R. rickettsii, and 1G rickettsiae do not
cross-react with R. australis [36]. Anacker et a1. [37] produced monoclonal antibodies to heat-sensitive and heatresistant protein antigens of R. rickettsii that cross-react with
R. sibirica, R. conorii, and R. montana but not with R. australis or R. akari. In a later study Li et al. [38] produced 38
monoclonal antibodies to R. rickettsii, R. conorii, and R.
sibirica. Most were species specific and protected animals
against lethal challenge with homologous strains. However,
some reacted with protein antigens from all SFG rickettsiae
tested, including R. akari and R. australis [38].
Monoclonal antibody specific for rickettsial SFG lipopolysaccharide-like antigen reacts with R. australis and with
all other SFG rickettsiae tested but not with 1G rickettsiae
[39]. Preparation of specific monoclonal antibodies to R. australis has not been reported, nor is it known whether epitopes
similar to those described for R. rickettsii exist in the case
of R. australis.
We are aware of only one in vitro study of the antimicrobial
susceptibility of R. australis. In a cumbersome embryonatedegg system, the growth of R. australis was inhibited by both
tetracycline and chloramphenicol [40]. In vitro testing of R.
australis against newer antibiotics (e.g., the quinolones) by
means of modem methods such as the plaque assay [41] and
the microplaque dye uptake assay [42] has not been reported.
881
882
Sexton et al.
Discussion
QfT is the least understood of the five rickettsial diseases
known to have occurred in Australia. Of these five diseases,
only epidemic typhus, which was imported with English con-
victs in the late eighteenth century [79, 80], is no longer present. Although one self-limiting epidemic occurred in Hobart,
Tasmania, in 1839, the temperate climate and uncrowded living conditions in Australia were not conducive to sustained
propagation of the etiologic agent, R. prowazekii [80]. Some
of earliest and best descriptions of murine typhus were made
by Australians [81-83], and small numbers of R. typhi infections continue to be reported in Australia. Q fever, first described in Brisbane by Derrick [84], remains both numerically
and economically the most important rickettsial disease in
Australia. The appellation Coxiella bumetii honors MacFarlane Burnet, one of Australia's three Nobel laureates in
science, who characterized the etiologic agent discovered by
Derrick [85, 86]. Scrub typhus was first recognized in Australia as one of the causes of "Mossman" or "coastal" fever
by Langan and Mathew in 1935 [87]. Subsequently, this disease has been identified as an endemic (and occasionally an
epidemic) problem in northern Queensland [9, 58, 88, 89].
SFG rickettsiae are found worldwide in areas ranging from
deserts to tropical rain forests, temperate forests, open plains,
and even alpine regions. Studies in Pakistan and China have
demonstrated that different SFG rickettsiae may coexist in the
same geographic area [90, 91]. Thus assumptions-based
solely on serologic testing-that the identity of an SFG agent
can be inferred from the location in which the associated illness arose may not be correct. Until careful studies using
proper methods are undertaken, it cannot be assumed that
pathogenic or nonpathogenic SFG rickettsiae other than R.
australis do not exist in Australia.
Prior failures to find R. australis in Australian ticks and
animals may be due to a very low rate of natural infection
among the ticks or other animals tested, sampling of the wrong
species, or the use of insufficiently susceptible strains of laboratory mice. The genetic background of the laboratory
mouse, the dose and strain of the rickettsiae, and the route
of inoculation all influence the odds of establishing lethal infection in mice. The dose required to produce disease in susceptible, inbred mice may vary by >500-fold among strains
of SFG rickettsiae [18]. Thus, previous unsuccessful attempts
to isolate R. australis during field studies should be interpreted
with caution.
The northern limit of R. australis is unknown. New Guinea
and its associated islands and the Indonesian archipelago are
close to northern Queensland and share many of its ecologic
features. A rickettsial isolate that was histologically dissimilar from R. tsutsugamushi was obtained from ticks (Dermacentor, Haemaphysalis, and Rhipicephalus species) removed from
a Sumatran wild boar [92]. Further information is needed on
the geographic limits of R. australis and of the other SFG
rickettsiae from the Eastern Hemisphere. Recently, the southern limits of R. sibirica have been extended [31, 93]; perhaps
the northern limits of R. australis will expand similarly as
further studies are done on the Malaysian and Indonesian archipelago.
The potential role of rabbits and of the unique marsupial
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Twenty-one other Ixodes species exist in Australia, as do
eight species of Haemaphysalis and 12 species of Amblyomma
[67]. Some of these species living in other parts of the world
and in nearby Malaysia are known to contain SFG rickettsiae
[69, 70]. Haemaphysalis humerosa and Amblyomma triguttatum are naturally infected with C. bumetti in Australia [59]
and readily bite humans [71], but neither species has been
found to harbor R. australis. Ixodes cornuatus, which readily bites humans in southeastern Victoria (authors' unpublished
observations), has not been examined for rickettsial infection.
Aponomma species are also numerous in Australia, as is the
imported tick Rhipicephalus sanguineus. The latter is a known
vector of R. rickettsii, R. conorii, and Rickettsia rhipicephali,
none of which is known to exist in Australia. An attempt to
transmit R. australis through R. sanguineus was unsuccessful;
the methods for this experiment have not been published [3].
Despite failures to isolate R. australis from small samples
of Haemaphysalis, Amblyomma, and Apnomma species,
pathogenic and nonpathogenic rickettsiae may exist in some
of these ticks. Detection of nonpathogenic organisms requires
examination of tick tissues or hemolymph with specific
fluorescent antibody conjugates and subsequent use of special methods of isolation. Studies utilizing these techniques
in the United States have shown that various SFG serotypes
coexist in restricted geographic areas. For instance, four SFG
species (one pathogenic, three nonpathogenic) were found in
ticks sampled from the Bitterroot Valley of western Montana
in 1981 [72]. Similar results were reported from California
and Connecticut [73, 74]. Neither studies employing the hemolymph test [75] nor those designed to look specifically for
nonpathogenic SFG rickettsiae in Australian ticks have been
reported. Either an ELISA used for the detection of R. typhi
in fleas [76] or polymerase chain reaction technology could,
if adapted to SFG rickettsiae in ticks, simplify field detection
of R. australis.
One report described the isolation of a "rickettsia-Iike'torganism (the R799 strain) from a water rat trapped in Brisbane in 1961 [77]. This organism, which morphologically
resembled R. tsutsugamushi, was shown to be distinct from
R. australis and other known rickettsiae in Australia by means
of animal cross-protection tests. With serial passage the strain
became mouse adapted, but it was discarded without being
further characterized (1. H. Pope, personal communication).
During experiments with the R799 strain, an apparently identical agent was isolated in the same laboratory from A. triguttatum ticks collected from sheep and cattle in western
Queensland [78]. Whether this organism exists in nature in
this or other tick species is unknown. Its ecologic relationship to R. australis, if any, is also unknown.
RID 1991;13 (September-October)
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Rickettsial Infections in Australia
nation "Australian spotted fever" may be more accurate, we
favor the continued use of the older term, "QTT."
Clustering of cases in households and discrete geographic
areas was observed in several instances. Approximately one
in eight cases occurred in an urban or suburban setting. A
similar urban/suburban acquisition has been described for R.
rickettsii infection in the United States [95]. Thus QTT, like
other tick-borne diseases, may occur in city or suburban
dwellers. As for Rocky Mountain spotted fever and other tickborne rickettsial infections, hyperendemic or focal areas are
likely to exist for R. australis infection.
The majority of patients with Mediterranean spotted fever
and Rocky Mountain spotted fever are <21 years old, whereas
in this series only 15 % of patients were <21 years old and
the average age was 31.7 years. Further studies are necessary
to determine whether this age difference between patients with
QTT and those with other spotted fevers is real or is due to
underdiagnosis of mild or inapparent infections in children.
With the increasing popularity of bush activities such as
camping, hiking, and fishing among tourists from within Australia and overseas, physicians in nonendemic areas need to
be aware of the clinical features of QTT. The importation of
infections due to R. conorii, R. tsutsugamushi, and R. typhi
by travelers is well recognized [96-98]; similar importations
of QTT could easily take place. In fact, 13 of the patients in
this series acquired their infections on holidays, and four were
treated in a state other than that in which their infection was
acquired.
QTT has been a notifiable disease in Australia for four decades yet frequently goes unreported. Many suspected cases
are not serologically confirmed. Forty cases in this series had
not been reported to state health departments. Our conversations with clinicians in endemic areas confirm that patients
with rash and fever are frequently observed or treated empirically with tetracycline without follow-up serologic testing.
Accurate data on the incidence of Australian rickettsial diseases are currently unavailable, as reporting systems are
neither effective nor standardized from state to state. Approximately 16.5 million people live in Australia-a land mass
nearly the size of the United States. If the incidence of QTT
were the same as that of Rocky Mountain spotted fever in the
United States (0.3/100,000) [99], only 50 cases would be expected annually. The recent marked increase in reports of typhus (all forms) to the Communicable Diseases Unit of the
Australian Department of Health may reflect the trend towards
an increasing incidence of rickettsial diseases seen in other
parts of the world [100]. Better surveillance systems and diagnostic methods, along with increased awareness among clinicians, can clarify whether or not this is the case and can
better define the full range of clinical illness due to R. australis. In addition, an active surveillance system like that used
by Wilfert et al. to study Rocky Mountain spotted fever in
an endemic area of the United States [101] could, if applied
to a QTT-endemic area such as Flinders Island, provide important data.
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fauna of Australia in the propagation and cycling of R. australis warrants further study. Opossums in the Western Hemisphere have sustained rickettsemia for 3-4 weeks after
experimental infection with the prototypic SFG species, R.
rickettsii [94]. Rabbits, which may playa role in the maintenance of SFG rickettsiae in North and South America [43,
44], have reproduced to huge numbers in Australia since their
introduction in the nineteenth century and could be important in the local ecology of SFG rickettsiae.
R. australis has not yet been isolated from patients, ticks,
or animals in locations outside Queensland, yet there is clinical, serologic, and epidemiologic evidence of human infection with SFG rickettsiae in at least three other Australian
states. As two known vectors for R. australis exist in these
regions, we presume that the cases from Flinders Island and
Victoria described by Stewart, Graves, Dwyer, and associates [10-12] are due to R. australis. Proof of this hypothesis
will require rickettsial isolation from humans, ticks, and
animals. Such efforts are currently under way.
The clinical and epidemiologic features of cases from southeastern Australia differed in several important respects from
those of cases from northeastern Australia (table 1). The frequency of tick bite, eschar, and lymphadenopathy varied between regions, as did the season of onset. The last finding
is most likely due to climatic differences. Spring and summer come 1-2 months earlier in Queensland and northern New
South Wales than farther south. Clinical data on cases from
Flinders Island were often incomplete, with rickettsial serologic studies done months or years after illness in some instances. Sera were tested from some patients from Flinders
Island who lacked a history of tick bite and classical clinical
symptoms of QTT. We suspect that cases from New South
Wales and Queensland were serologically confirmed only if
patients had one or more typical findings (e.g., tick bite, eschar, or lymphadenopathy). Indeed, all differences but one
(the frequency of tick bite) disappeared when the clinical'and
epidemiologic features of 14 serologically confirmed cases
from Flinders Island and Victoria in which spotted fever was
suspected early in the course of care were compared with those
of similar cases from Queensland and New South Wales (table 2). The lower frequency of tick bite in the former group
could be secondary to the presence of different tick vectors
in the two regions. I. holocyclus is easily detected after biting
humans [66], while other species may be less apparent during feeding. The similarity of clinical and epidemiologic features, the continuous geographic distribution of cases along
the entire eastern coast of Australia, and the known distribution of I. holocyclus and I. tasmani support the hypothesis
that R. australis is responsible for all 62 reviewed cases. The
characterization of additional clinical isolates is of primary
importance to an understanding of the etiology of this infection. R. rickettsii and R. sibirica were first described in isolated geographic areas, yet later were shown to have a much
wider distribution. We anticipate the same expansion of the
recognized range of R. australis infection. Although the desig-
883
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Sexton et al.
tick typhus and Mediterranean spotted fever, QTT may include tender lymphadenopathy and a local eschar. Like Rocky
Mountain spotted fever and Mediterranean spotted fever, QfT
may occasionally occur without a detectable rash [105-108].
Also as in Rocky Mountain spotted fever and other tick-borne
SFG rickettsial diseases, a history of tick bite may be absent.
Diagnosis is easiest for patients with tick bite and eschars,
but the presence of fever and headache and a history of exposure to a tick-infested environment justify the initiation of
therapy, with subsequent serologic testing.
Like those on the five other populated continents, SFG rickettsiae in Australia probably have a more complex ecology
and epidemiology than is currently recognized. Furthermore,
as more cases are diagnosed, the spectrum of clinical features
and complications will probably be expanded.
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days).
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Rickettsial Infections in Australia
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