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ABSTRACT |
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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Orientia tsutsugamushi, the causative agent of scrub typhus, is a gram-negative intracellular pathogen.11 Scrub typhus is a common zoonotic disease of rural Asia and the Western Pacific islands, transmitted by infected larval trombiculid mites, and characterized by general malaise, fever, headache, myalgias, conjunctival suffusion, cough, rash, regional lymphadenopathy, and eschar formation. Relative bradycardia is mentioned in reports of scrub typhus case series from the preantibiotic era,12,13 but it was not the primary focus of these reports and was not quantified. A description of scrub typhus in 32 cases contracted during the Vietnam War noted a prevalence of 97%, but a definition of relative bradycardia was not provided.14 In a somewhat more recent report, relative bradycardia was said to occur in 40% of the cases, again without a specific definition, and no details were given.15 We therefore prospectively examined 100 febrile patients with documented scrub typhus to further define the relationship between heart rate and temperature in this condition.
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MATERIALS AND METHODS |
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Data acquisition.
Oral temperature and heart rate data were recorded upon presentation, during antibiotic treatment, and following symptom resolution. Fever was defined as an oral temperature 
37.8°C. Febrile heart rate and temperature data represent the vital signs documented on initial patient evaluation, before the application of antibiotic therapy. Baseline temperature and heart rate were assessed when patients first became and then remained afebrile following treatment. Although no uniform definition of relative bradycardia exists, we defined it a priori as an increase in the heart rate from a baseline of <10 beats/minute/1°C increase in temperature.7 Patients exhibiting a pulse increase 10 beats/minute/°C were classified as having a normal pulse increase (NPI). Infection with O. tsutsugamushi was diagnosed serologically by a dot-blot rapid enzyme-linked immunosorbent assay (DipSticks; Integrated Diagnostics, Baltimore, MD) and confirmed by an indirect immunoperoxidase test if IgM antibody titers were >1:400 or IgG titers were >1:1,600.
Statistical analysis. Data are expressed as the median (interquartile range [IQR]). Comparison of continuous variables between the NPI and relative bradycardia groups was performed using a Mann-Whitney rank sum test. A chi square analysis was used to compare independent proportions between groups. Statistical analyses were performed with Prism 3.0 software (GraphPad Software, San Diego, CA). A P value of 0.05 was considered statistically significant.
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RESULTS |
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. The age range was 18–68 years and 54% were men. Fifty-three patients (53%) responded to fever with a heart rate increase 
10 beats/minute/°C (relative bradycardia group), the majority of whom (62%) did not mount a response greater than 7.5 beats/minute/°C. The remaining 47 patients had a heart rate response 10 beats/minute/°C (NPI group). The median (IQR) heart rate response for the entire febrile scrub typhus population was 9.3 (6.3–12.5) beats/minute/°C. Interestingly, 65% of the entire O. tsutsugamushi-infected population had a febrile heart rate <100 beats/minute on presentation.
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). Despite differences in the resting heart rate between the relative bradycardia and NPI patients, there was no significant linear relationship between resting heart rate and the cardiac response to infection (R2 = 0.10; Figure 1B).
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38.9°C) showed that the median peak temperatures in the NPI (n = 30) and relative bradycardia (n = 27) groups were 39.3 (38.95–39.85)°C and 39.6 (39.20–40.00)°C, respectively (P = 0.11). The median heart rate response for these 57 patients was 10.0 (6.9–13.0) and the prevalence of relative bradycardia in this subgroup remained high (47%). |
DISCUSSION |
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102°F might be insufficient to discern pulse temperature abnormalities.10 Our assessment of this more febrile subgroup yielded similar results to those of the entire study population.
Although the group of patients exhibiting relative bradycardia during scrub typhus had a higher resting heart rate than did those who mounted a normal, febrile heart rate increase, the basal heart rate for a given patient was not predictive of their febrile heart rate response. The factors determining an individual’s cardiovascular response during fever are complex and not fully understood.2 During the febrile response, a decrease in systemic vascular resistance is accompanied by an increase in the heart rate aimed at maintaining/ enhancing cardiac output.4,5 In addition, pyrexia itself may induce tachycardia through thermal effects upon the sinus node.2 Cytokines elaborated during infection, such as tumor necrosis factor (TNF)-
, interleukin-1ß (IL-1ß) and IL-6, may also directly alter a patient’s hemodynamic status, independent of effects of warmth.2 In this regard, it is interesting that relative bradycardia has been found to occur during typhoid fever,7 an infection that can be accompanied by a depressed ability of peripheral blood leukocytes to release proinflammatory cytokines such as TNF- and IL-1ß.17 However, a study assessing the relationship between cytokine levels and the heart rate response during typhoid fever has not been conducted.
Whether relative bradycardia occurs more commonly in scrub typhus than in other relative bradycardia–associated infections is unclear, since differences in study design, sample size, and definition of relative bradycardia make comparison among studies difficult. Our definition of a relatively slow cardiac response to pyrexia of <10 beats/minute/°C represents the lower end of the normal febrile heart rate increase of 10–18 beats/minute/°C during infectious and noninfectious fever.1,3–6 This definition of relative bradycardia has been applied to other patient populations.7 However, the application of alternative definitions of relative bradycardia would greatly affect our results. For example, other investigators have defined relative bradycardia as a cardiac response of <10 beats/minute/°F (18 beats/minute/°C) in the setting of scrub typhus.12 The prevalence of relative bradycardia in our population increases from 53% to 92% when this cut-off value is used. Conversely, if a definition of 8.5 beats/minute/ °C as the normal cardiac response to fever is used, as reported in a small study of ill young men,18 the prevalence of relative bradycardia in our cohort would decrease to 40%.
The microbial and/or host factors responsible for eliciting a relatively slow pulse response to infection are not well understood. The majority of organisms reported to be associated with relative bradycardia are intracellular pathogens. It is speculative that an occult intracellular habitat might alter neural or humoral signals regulating heart rate during infection. Orientia tsutsugamushi is atypical as a gram-negative organism in that it lacks both peptidoglycan and lipopolysaccharide.11 Whether these structural differences might alter the cardiovascular response of an infected host is unclear. In addition, the clinical significance of relative bradycardia during infection is unknown.
In summary, clinically mild infection with O. tsutsugamushi is often associated with relative bradycardia. The discovery of relative bradycardia in a febrile patient at risk for scrub typhus should alert health care providers to this diagnosis. Further studies are required to understand the clinical significance of relative bradycardia in scrub typhus. The development of a standard definition of relative bradycardia may aid in the design of future investigations.
Received October 2, 2002. Accepted for publication January 9, 2003.
Acknowledgment: This work was presented in part at the 40th Annual Meeting of the Infectious Diseases Society of America, Chicago, October 2002.
Financial support: This study was supported by the U.S. Army Research and Material Command and the Royal Thai Army.
Disclaimer: The opinions or assertions contained in this report are the private views of the investigators and are not to be construed as official or reflecting the views of the U.S. Army or the Royal Thai Army.
Authors’ addresses: David M. Aronoff, Divisions of Infectious Diseases and Pulmonary and Critical Care Medicine, University of Michigan Health System, 6301 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0642, Telephone: 734-763-9077, Fax: 734-764-4556, E-mail: daronoff{at}umich.edu. George Watt, HIV Interaction Section, Retrovirology Department, Armed Forces Research Institute of Medical Sciences, APO AP 96546, Telephone: 66-2-644-6735, Fax: 66-2-246-8908, E-mail: wattgh{at}thai.amedd.army.mil or gwattth{at}yahoo.com
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) and NPI patients (•).