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Am. J. Trop. Med. Hyg., 68(4), 2003, pp. 477–479
Copyright © 2003 by The American Society of Tropical Medicine and Hygiene
PREVALENCE OF RELATIVE BRADYCARDIA IN
ORIENTIA TSUTSUGAMUSHI INFECTION
DAVID M. ARONOFF AND GEORGE WATT
Divisions of Infectious Diseases and Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Health
System, Ann Arbor, Michigan; Retrovirology Department, United States Army Military Component, Armed Forces Research Institute
of Medical Sciences, Bangkok, Thailand
Abstract. We investigated 100 febrile patients infected with Orientia tsutsugamushi (the etiologic agent of scrub
typhus) for the presence of relative bradycardia, defined as in increase in heart rate of < 10 beats/minutes/1°C increase
in temperature. The median heart rate response for the entire febrile scrub typhus population was 9.3 beats/minute/°C
and the prevalence of relative bradycardia was 53%. The occurrence of relative bradycardia was independent of patient
age or gender. There were no differences in median basal temperature or febrile temperature between those patients
exhibiting relative bradycardia and those with a normal febrile pulse increase. However, febrile patients with relative
bradycardia had a significantly higher resting pulse rate following recovery from infection than did patients who had a
normal pulse increase during their illness. These data demonstrate that relative bradycardia frequently accompanies mild
infection with O. tsutsugamushi and that baseline cardiovascular parameters may affect the febrile heart rate response
to scrub typhus.
ferral center. Patient selection was performed as previously
described.16 Eligible patients were ambulatory adults without
hypotension, shock, impaired consciousness, or pulmonary
dysfunction. Additional exclusion criteria were vomiting,
presence of a febrile illness other than infection with O. tsutsugamushi, a serum bilirubin concentration >25.7 ␮mol/L, an
alanine aminotransferase concentration >100 units/L, and ingestion of acetaminophen, nonsteroidal anti-inflammatory
drugs, chloramphenicol, tetracycline, or ciprofloxacin during
the 48-hour period before evaluation. No patients were receiving treatment with beta-blockers. Study participants gave
written informed consent according to a protocol approved by
the U.S. Army Scientific and Human Use Review and Regulatory Affairs Division and by the Thai Ministry of Public
Health Human Use Committee.
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 ⱖ37.8°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 ⱖ10
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.
INTRODUCTION
During infection, there tends to be a close degree of relationship between pulse rate and temperature.1,2 The usual
heart rate increase in response to microbial invasion or exogenously administered, noninfectious pyrogens ranges from
10 to 18 beats/minute/1°C increase in temperature, although
there is considerable individual variation.1,3−6 Relative bradycardia, an unexpectedly low heart rate response for a given
increase in temperature, has been reported as a feature of a
number of infectious diseases, particularly those caused by
intracellular gram-negative organisms. This pulse-temperature dissociation has been associated with typhoid fever, Legionnaire’s disease, babesiosis, Q fever, infection with Rickettsia sp., malaria, leptospirosis, pneumonia caused by Chlamydia sp., and viral infections such as dengue fever, yellow
fever, and viral hemorrhagic fevers.7−10 Neither the microbial
and/or host factors responsible for a relatively slow pulse response to infection nor the clinical significance of relative
bradycardia are known.
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.
MATERIALS AND METHODS
Study population. The study was conducted in northern
Thailand at Chiangrai Regional Hospital, a tertiary-care re-
477
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ARONOFF AND WATT
TABLE 1
Characteristics of 100 patients with scrub typhus*
Patient characteristic
Normal pulse increase
(n ⳱ 47)
Relative bradycardia
(n ⳱ 53)
P
Age (years)
Males (%)
Basal temperature (°C)†
Febrile temperature (°C)
Basal heart rate (beats/minute)†
Febrile heart rate (beats/minute)
32 (25–39)
53
36.9 (36.7–37.1)
38.9 (38.7–39.6)
66 (61–76)
100 (89–114)
33 (27–50)
55
36.8 (36.6–37.1)
39.0 (38.4–39.7)
75 (65–84)
88 (80–96)
0.21
0.88
0.30
0.65
0.04
<0.0001
* Values are the median (interquartile range) unless otherwise indicated.
† Baseline temperature and heart rate were assessed when patients first became and then remained afebrile following treatment.
RESULTS
Pulse and temperature changes provoked by infection with
O. tsutsugamushi. The dynamic relationship between heart
rate and an increase in temperature was assessed in 100 febrile patients infected with O. tsutsugamushi. The characteristics of these patients are summarized in Table 1. The age
range was 18−68 years and 54% were men. Fifty-three patients (53%) responded to fever with a heart rate increase
ⱕ10 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 ⱖ10 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.
Basal (resting) and febrile temperatures were not significantly different between patients exhibiting relative bradycardia or NPI. Although patients exhibiting relative bradycardia
had a higher median resting heart rate than did patients who
responded to scrub typhus with a normal heart rate response
(75 versus 66 beats/minute; P ⳱ 0.04), the opposite effect was
seen during fever, with patients with relative bradycardia
achieving significantly lower heart rates than the NPI cohort
(88 versus 100 beats/minute; P < 0.0001) (Figure 1A). Despite
differences in the resting heart rate between the relative bra-
dycardia and NPI patients, there was no significant linear
relationship between resting heart rate and the cardiac response to infection (R2 ⳱ 0.10; Figure 1B).
An analysis of patients with higher degrees of fever (temperature ⱖ38.9°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
Our findings support previous reports that relative bradycardia occurs in scrub typhus12−15 and quantify its frequency
and magnitude. In this study of 100 serologically documented
patients with O. tsutsugamushi infections, we found that the
prevalence of relative bradycardia was 53%, a feature independent of patient age or gender. In addition, the majority of
the patients with scrub typhus had a heart rate <100 beats/
minutes on presentation with pyrexia. It has been suggested
that the term relative bradycardia should only be applied to
patients with a temperature >102°F (38.9°C), since differences between heart rate and temperature readings ⱕ102°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.
FIGURE 1. A, Change in heart rate (HR) during acute scrub typhus infection. The upper limit of the bars represents the median febrile HR
measured during acute infection with Orientia tsutsugamushi in patients with a relative bradycardia (RB) response to infection (n ⳱ 53) and
patients with a normal pulse increase (NPI) (n ⳱47). The lower limit of the bars represents the median basal HR measured following recovery
from infection. * P < 0.05, ** P < 0.0001 for comparison with the RB group. B, Relationship between resting HR and the pulse response to fever
for RB patients (䊊) and NPI patients (䊉).
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RELATIVE BRADYCARDIA IN SCRUB TYPHUS
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-1␤ (⌱L-1␤) 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-1␤.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: [email protected]. 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: [email protected].
army.mil or [email protected]
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