DIFFERENTIATING DENGUE VIRUS INFECTION FROM SCRUB TYPHUS IN THAI

ADULTS WITH FEVER

GEORGE WATT, KRISADA JONGSAKUL, CHAROEN CHOURIYAGUNE, AND ROBERT PARIS
Department of Retrovirology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand; Department of Internal
Medicine, Chiangrai Regional Hospital, Chiangrai, Thailand
Abstract. Dengue fever and scrub typhus are common infections in Asia that often present as acute febrile illness of
unclear etiology. We prospectively evaluated febrile adults presenting to the outpatient department of a hospital in
northern Thailand to attempt to identify distinguishing characteristics between the two infections. Fifty-four patients
were infected with scrub typhus and 35 were infected with dengue virus. Dengue virus infection was associated with
hemorrhagic manifestations, particularly bleeding from the gums, which was reported by 27% of the dengue patients, but
by none of the scrub typhus patients (P < 0.001, by Fishers exact test). A low platelet count (< 140,000/mm
3
) and low
white blood cell count (< 5,000/mm
3
) were strongly associated with dengue infections: odds ratio 26.3 (95% confi-
dence interval [CI] 7.493.2) for platelet count and 8.2 (95% CI 2.625.5) for leukocyte count. Prospective
evaluations of the usefulness of these simple criteria to differentiate scrub typhus from dengue infection are needed in
other areas, particularly where rapid confirmatory diagnostic tests are not available.
INTRODUCTION
Dengue fever is common in Asian adults and often presents
as an acute febrile illness of unclear origin.
15
Orientia tsut-
sugamushi, the etiologic agent of scrub typhus, is also a com-
mon cause of acute febrile illness of unclear origin in Asia.
6
We therefore prospectively collected data on admission clini-
cal and laboratory findings from adult Thai patients with den-
gue fever or scrub typhus to identify potentially useful pa-
rameters for differentiating these two infections.
MATERIALS AND METHODS
Adult, febrile patients seronegative for human immunode-
ficiency virus who presented to Chiangrai Regional Hospital
in northern Thailand during the rainy season of 1991 and
provided informed consent were tested for scrub typhus and
dengue virus. Standardized code sheets were completed and
complete blood counts were made in individuals with less
than two weeks of fever, no malarial parasites, no known
chronic medical problems, and no history of acquired immu-
nodeficiency syndromedefining illnesses.
IgM and IgG antibodies to dengue virus (any of the four
serotypes, not distinguished by the serologic test) and Japa-
nese encephalitis virus were measured at the acute stage and
four weeks later by an antibody-capture enzyme immunoas-
say.
7
Recent (occurring in the previous two months) flavivirus
infection was diagnosed for any individual with an IgM result
> 40 units. Infection was classified as due to dengue virus or
Japanese encephalitis virus depending on the relative
amounts of virus-specific IgM.
7
Scrub typhus was diagnosed if
indirect immunoperoxidase IgG antibody titers were 1:
1,600 or IgM titers were 1:400 in a single acute specimen, or
if there was a four-fold or greater increase in antibody titer
between acute and convalescent serum samples.
8
Statistical
analyses were performed using Fishers exact test for cat-
egorical variables and the Mann-Whitney U test for continu-
ous variables.
RESULTS
During the four-month study period, 54 patients were di-
agnosed with O. tsutsugamushi infection, and nine died.
Thirty-five dengue virus infections were confirmed, and there
was one death. The patient who died was initially not sus-
pected of having dengue, was discharged from hospital, and
then returned with irreversible shock secondary to upper gas-
trointestinal bleeding. The admission characteristics of pa-
tients with scrub typhus were similar to those with dengue
fever (Table 1). However, dengue patients had a shorter fever
history (median 4 days, range 211 days) than individu-
als with scrub typhus (median 9 days, range 214 days;
P < 0.001, by Mann-Whitney U test). Hemorrhagic manifes-
tations were more common in dengue patients (53% versus
13%; P < 0.001, by Fishers exact test).
The median platelet count (Figure 1) in the patients with
dengue (72,000/mm
3
, interquartile range (IQR) 40,000
90,000/mm
3
) was significantly lower than that for the scrub
typhus group (median 206,000/mm
3
, IQR 142,000
240,000/mm
3
; P < 0.001, by Mann-Whitney U test). The me-
dian white blood cell count in dengue patients (4,950/mm
3
,
IQR 3,5006,200/mm
3
) was also lower than that of the
individuals infected with O. tsutsugamushi (9,600/mm
3
, IQR
5,90012,200/mm
3
; P < 0.001, by Mann-Whitney U test).
Median hematocrit was higher in the dengue group (43.0%,
IQR 40.049.0%) than in the scrub typhus group (38.5%,
IQR34.042.0%; P < 0.001, by Mann-Whitney U test). The
age-adjusted odds ratios (ORs) were 26.3 (95% confidence
interval [CI] 7.493.2) for the association of a platelet
TABLE 1
Characteristics on admission of the patients studied
Dengue
(n 35)
Scrub typhus
(n 54)
Median age, years (range) 31 (1656) 35 (1673)
median days of fever (range) 4 (211) 9 (214)*
Males 21 (60%) 32 (59%)
Indoor occupation (student,
housewife, office work) 18 (51%) 8 (15%)*
Lymphadenopathy 23 (66%) 40 (74%)
Hemorrhagic manifestations 19 (54%) 7 (13%)*
Bleeding gums 9 (26%) 0*
Epistaxis 3 (9%) 3 (6%)
Hematemesis and/or melena 2 (6%) 1 (2%)
Erythematous rash 5 (14%) 2 (4%)
Pettechiae and/or eccymoses 3 (9%) 2 (4%)
* P < 0.01.
Am. J. Trop. Med. Hyg., 68(5), 2003, pp. 536538
Copyright 2003 by The American Society of Tropical Medicine and Hygiene
536
count less than 140,000/mm
3
and dengue and 8.2 (95% CI
2.625.5) for the association of a leukocyte count less than
5,000/mm
3
and dengue.
DISCUSSION
The results of this investigation are consistent with anec-
dotal reports that both scrub typhus and dengue virus infec-
tions are common causes of acute febrile illness of unclear
origin in Chiangrai in northern Thailand, and affirm the im-
portance of dengue as an infection of Asian adults. Diagnostic
test results, even when available, rarely arrive in time to affect
treatment decisions in areas endemic for dengue and scrub
typhus. However, our study results indicate potentially useful
distinguishing features between the two infections. Hemor-
rhagic manifestations were more common with dengue (Table
1), and bleeding from the gums was reported only by dengue
patients (27% versus 0%; P < 0.001, by Fishers exact test).
Median platelet counts were significantly lower in dengue
patients: the OR for a count less than 140,000/mm
3
was 26.3
(95% CI 7.493.2). The OR for the association of a leu-
kocyte count less than 5,000/mm
3
and dengue was 8.2 (95%
CI 2.625.5).
Our study findings are useful for clinicians working in areas
where dengue and scrub typhus are common. At Chiangrai
hospital, scrub typhus and dengue infection are the two most
frequently listed presumptive diagnoses in patients who
present with fever of unclear etiology. Early management of
acute nonspecific febrile illnesses at this hospital is based on
an estimation of which of these two diagnoses is more likely.
The objective markers we report could therefore help patient
management. There is currently no specific antiviral therapy
for dengue virus infection, but the introduction of intensive
intravenous fluid replacement in dengue shock syndrome led
to a marked reduction in the mortality rate in pediatric cen-
ters in Southeast Asia from approximately 20% to 2%.
9
Pa-
tients suspected of dengue fever can be monitored closely in
the hospital for upper gastrointestinal bleeding,
1
the cause of
death in the dengue-infected patient in our series. Suspicion
of scrub typhus permits early antibiotic treatment, which re-
duces the mortality of infection with O. tsutsugamushi.
6
De-
layed diagnosis is likely to have contributed to the high case
fatality rate for scrub typhus in this series, although antibiotic
resistance may also have played a role.
10,11
Our findings suggest ways for clinicians to distinguish be-
tween these two infections, but they must be confirmed by
FIGURE 1. Complete blood count results in 54 patients with scrub typhus and 35 patients with dengue virus infection. The shaded boxes outline
the 70th percentiles of each variable and the medians are indicated by the horizontal lines. The error bars show the upper and lower 90th
percentiles. Platelets and leukocytes are per mm
3
and hematocrit (HCT) is expressed in %. Note that few scrub typhus patients have platelet
counts < 140,000/mm
3
or leukocyte counts < 5,000/mm
3
. WBCs white blood cells.
DENGUE AND SCRUB TYPHUS IN THAI ADULTS 537
prospective studies in other regions of Asia. Simple objective
measures could increase the clinical suspicion of these two
infections and thereby lower their morbidity and mortality in
areas where rapid diagnostic tests are not available. However,
potentially life-saving antibiotics should not be withheld un-
less scrub typhus is certain to be absent.
Received October 14, 2002. Accepted for publication January 27,
2003.
Authors addresses: George Watt, Krisada Jongsakul, and Robert
Paris, Department of Retrovirology, Armed Forces Research Insti-
tute of Medical Sciences, APO AP 96546, Bangkok, Thailand, Tele-
phone: 66-2-644-6735, Fax: 66-2-246-8908, E-mail: wattgh@thai.
amedd.army.mil. Charoen Chouriyagune, Department of Internal
Medicine, Chiangrai Regional Hospital, Chiangrai, Thailand.
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