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DIFFERENTIATING DENGUE VIRUS INFECTION FROM SCRUB TYPHUS IN THAIADULTS WITH FEVER

GEORGE WATT, KRISADA JONGSAKUL, CHAROEN CHOURIYAGUNE, AND ROBERT PARISDepartment 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 innorthern Thailand to attempt to identify distinguishing characteristics between the two infections. Fifty-four patientswere infected with scrub typhus and 35 were infected with dengue virus. Dengue virus infection was associated withhemorrhagic manifestations, particularly bleeding from the gums, which was reported by 27% of the dengue patients, butby none of the scrub typhus patients ( P < 0.001, by Fishers exact test). A low platelet count (< 140,000/mm 3 ) and lowwhite 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. Prospectiveevaluations of the usefulness of these simple criteria to differentiate scrub typhus from dengue infection are needed inother 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 Hospitalin northern Thailand during the rainy season of 1991 andprovided informed consent were tested for scrub typhus and

dengue virus. Standardized code sheets were completed andcomplete blood counts were made in individuals with lessthan two weeks of fever, no malarial parasites, no knownchronic medical problems, and no history of acquired immu-nodeficiency syndromedefining illnesses.

IgM and IgG antibodies to dengue virus (any of the fourserotypes, not distinguished by the serologic test) and Japa-nese encephalitis virus were measured at the acute stage andfour weeks later by an antibody-capture enzyme immunoas-say. 7 Recent (occurring in the previous two months) flavivirusinfection was diagnosed for any individual with an IgM result> 40 units. Infection was classified as due to dengue virus orJapanese encephalitis virus depending on the relativeamounts 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, orif there was a four-fold or greater increase in antibody titerbetween acute and convalescent serum samples. 8 Statisticalanalyses 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 therewas one death. The patient who died was initially not sus-pected of having dengue, was discharged from hospital, andthen returned with irreversible shock secondary to upper gas-trointestinal bleeding. The admission characteristics of pa-tients with scrub typhus were similar to those with denguefever (Table 1). However, dengue patients had a shorter feverhistory (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% versus13%; P < 0.001, by Fishers exact test).

The median platelet count (Figure 1) in the patients withdengue (72,000/mm 3 , interquartile range (IQR) 40,00090,000/mm 3 ) was significantly lower than that for the scrubtyphus group (median 206,000/mm3 , IQR 142,000240,000/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/mm3 ) was also lower than that of theindividuals 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%,IQR 34.042.0%; P < 0.001, by Mann-Whitney U test). Theage-adjusted odds ratios (ORs) were 26.3 (95% confidenceinterval [CI] 7.493.2) for the association of a platelet

TABLE 1Characteristics 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. 536538Copyright 2003 by The American Society of Tropical Medicine and Hygiene

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count less than 140,000/mm 3 and dengue and 8.2 (95% CI2.625.5) for the association of a leukocyte count less than5,000/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 unclearorigin in Chiangrai in northern Thailand, and affirm the im-portance of dengue as an infection of Asian adults. Diagnostictest results, even when available, rarely arrive in time to affecttreatment decisions in areas endemic for dengue and scrubtyphus. However, our study results indicate potentially usefuldistinguishing features between the two infections. Hemor-rhagic manifestations were more common with dengue (Table1), and bleeding from the gums was reported only by denguepatients (27% versus 0%; P < 0.001, by Fishers exact test).Median platelet counts were significantly lower in denguepatients: 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 areaswhere dengue and scrub typhus are common. At Chiangraihospital, scrub typhus and dengue infection are the two mostfrequently listed presumptive diagnoses in patients whopresent with fever of unclear etiology. Early management of acute nonspecific febrile illnesses at this hospital is based onan estimation of which of these two diagnoses is more likely.The objective markers we report could therefore help patientmanagement. There is currently no specific antiviral therapyfor dengue virus infection, but the introduction of intensiveintravenous fluid replacement in dengue shock syndrome ledto 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 inthe hospital for upper gastrointestinal bleeding, 1 the cause of death in the dengue-infected patient in our series. Suspicionof 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 casefatality rate for scrub typhus in this series, although antibioticresistance 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 outlinethe 70th percentiles of each variable and the medians are indicated by the horizontal lines. The error bars show the upper and lower 90thpercentiles. Platelets and leukocytes are per mm 3 and hematocrit (HCT) is expressed in %. Note that few scrub typhus patients have plateletcounts < 140,000/mm 3 or leukocyte counts < 5,000/mm 3 . WBCs white blood cells.

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prospective studies in other regions of Asia. Simple objectivemeasures could increase the clinical suspicion of these twoinfections and thereby lower their morbidity and mortality inareas 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 RobertParis, 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 InternalMedicine, Chiangrai Regional Hospital, Chiangrai, Thailand.

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