Tick-Borne Febrile Illnesses Lacking Specific Symptoms

CASE REPoRT
When time is ‘ticking’ away, don’t be clueless;
severity of illness Is a diagnostic clue
Tick-Borne Febrile Illnesses Lacking
Specific Symptoms
by William V. Stoecker, MD, David A. Calcara, BS, Joseph M. Malters, MD,
Monica Clonts, RN, BSN & E. Dale Everett, MD
When treatment is
delayed, some patients
can progress to severe
multisystem disease
with toxic shock-like
syndrome.
William V. Stoecker, MS, MD, MSMA
member since 1984, is a Clinical
Assistant Professor, Division of
Dermatology, at the University of
Missouri School of Medicine, and
practices dermatology in Rolla.
David A. Calcara, BS, is a first-year
medical student at the University of
Missouri School of Medicine. Joseph
M. Malters, MD, MSMA member
since 2003, practices dermatology
in Rolla. Monica Clonts, RN, BSN, is
a nurse at the Phelps County Health
Department. E. Dale Everett, MD,
is Emeritus Professor of Infectious
Diseases, Department of Internal
Medicine, University of Missouri
School of Medicine.
Contact: wvs@mst.edu
304 w July/August 2009 w 106:4 Missouri Medicine
Abstract
We report here one case of
tularemia, one case of human
monocytic ehrlichiosis, and
one case of febrile illness most
consistent with tularemia with
titers suggestive of Rocky
Mountain spotted fever in
residents of three south-central
Missouri counties. All three
cases had with nonspecific
symptoms of a febrile illness. All
three patients had a history of
a tick bite, common in southcentral
Missouri, but only
two patients reported the tick
bite when first seen. In these
three cases, the severity of the
illness provided a clue that led
to a diagnosis of tick-borne
febrile illnesses by confirmatory
serology in two cases. It is very
important that physicians be
aware of these diseases in the
spring and summer months.
Introduction
Missouri has a high incidence
of three tick-borne febrile illnesses:
Rocky Mountain spotted fever,
tularemia, and human monocytic
ehrlichiosis. In the diagnosis of these
tick-borne febrile illnesses, it is often
helpful to have specific signs and/
or laboratory findings. For Rocky
Mountain spotted fever, a purpuric
exanthem is the most prominent
finding leading to the diagnosis. For
tularemia, one of the most useful
signs is lymphadenopathy. For
ehrlichiosis, the combination of
leukopenia and thrombocytopenia
can serve to suggest this diagnosis
rather than other tick-borne
illnesses. However, patients may
lack these findings in the early stages
of their illness.
We present a series of three
patients who presented with
severe but nonspecific findings of
their illness. In all subjects, the
initial serologic studies were nondiagnostic,
as is routinely the case.
Convalescent serology established the
diagnosis in two of these cases.

Table 1. Case Definitions of Three Causes of Tick-Borne Febrile Eruptions1
Table 1
Case Definitions of Three Causes of Tick-Borne Febrile Eruptions 1
Name Clinical Presentation Laboratory Results
Ehrlichiosis Fever and one or more of the following:
Headache
Myalgia
Anemia
Leukopenia
Thrombocytopenia
Any hepatic transaminase elevation.
Rocky Mountain
Spotted Feve r
Case One: Undiagnosed
Acute Febrile Illness
In July, 2007, a 49-year-old male
presented at an urgent care clinic in
Jefferson City with a one-day history
of fever, headache, severe myalgia
and profuse sweating. During the
preceding day, he changed clothes
several times because he was sweating
so profusely that his “clothes kept
getting soaked.” He said, “no
one ever wants to feel as bad as I
did.” Six days previously, he was
bitten by a tick. On examination,
he had a temperature of 101° F.
and a small red macule on the
Fever and one or more of the following:
Rash
Headache
Myalgia
Anemia
Thrombocytopenia
Any hepatic transaminase elevation.
Tularemia One or more of the following:
Evidence or history of a tick or deerfly bite
Exposure to tissues of a mammalian host of
F.tularensis,
Exposure to potentially contaminated water.
Common symptoms:
Skin ulcers
Swollen
Painful lymph glands
Inflamed eyes
Sore throat
Mouth sores
Diarrhea
Pneumonia
If the bacteria are inhaled, symptoms can include
abrupt onset of fever, chills, headache, muscle
aches, joint pain, dry cough, and progressive
weakness.
People with pneumonia can develop chest pain,
difficulty breathing, bloody sputum, and
respiratory failure.
right groin area, the site of the
tick bite. Rash, pharyngitis, and
lymphadenopathy were absent.
No laboratory evaluations were
performed. A diagnosis of possible
tick-related illness was made and
therapy with doxycycline 100 mg
b.i.d. for 10 days was initiated.
Although his symptoms were greatly
improved after 24-48 hours of
antibiotic therapy, some degree of
fever, headache, malaise and myalgia
persisted. On the third day of
illness, the patient was seen at his
physician’s office with a fever of
100.4° F. Gentamicin 80 mg IM
Tick-Borne Febrile Illness Severity Page 11
Fourfold change in Ig-G-specific antibody
titer or
Detection of E. chaffeensis DNA in clinical
specimen or
Demonstration of ehrlichial antigen in a
biopsy sample by immunohistochemical
methods or
Isolation of E. chaffeensis from a clinical
specimen in cell culture
Fourfold change in Ig-G-specific antibody
titer or
Detection of R. rickettsii DNA in clinical
specimen or
Demonstration of spotted fever group
antigen in a biopsy sample by
immunohistochemical methods or
Isolation of R. rickettsii from a clinical
specimen in cell culture
Isolation of F. tularensis in a clinical specimen
or
Fourfold or greater change in serum
antibody titer to F. tularensis antigen
was given. On the fourth day of
illness, he returned to his physician’s
office, with unabated symptoms. His
temperature was 98.2 F. (after taking
acetaminophen). He was found to
have a swollen lymph node in the
right groin area. He received another
dose of gentamicin 80 mg IM. At
this time, an immunofluorescent
antibody immunoglobulin G titer
for Rocky Mountain spotted fever
(RMSF IgG-IFA) was obtained.
On the thirteenth day after illness
onset, the patient returned to his
physician’s office, and stated that all
symptoms had resolved and he felt
106:4 Missouri Medicine w July/August 2009 w 305

well. The RMSF IgG-IFA result was
1:128. An additional 10-day course
of doxycycline, 100 mg b.i.d., was
initiated. The convalescent RMSF
serology was not obtained. The
case was clinically most compatible
with ulceroglandular tularemia,
with a single serology suggestive of
RMSF. Without convalescent RMSF
serology or any testing for tularemia,
a diagnosis could not be made. 1
Case Two:
Confirmed Tularemia
In June, 2008, a 67-yearold
male Phelps County resident
attended a dermatology clinic for a
routine skin follow-up examination.
He had been “doing yard work”
four to five days before the onset of
illness. On the first day of illness, he
had vomited once. On the second
day of illness, he had awakened
with a headache, nausea, and chills,
progressing to further vomiting and
worsening prostration. On a clinic
visit on the second day, he had a
temperature of 100.3º Fahrenheit,
pulse of 96, and a blood pressure of
128/88, and felt too ill to stay to see
the physician. On the third day of
illness, his wife partially removed a
tick from the left upper back, later
identified from an Internet image
as a lone star tick (Amblyomma
americanum, adult female). On
the fourth day of illness, the fever
reached 103º F and prostration
became so severe that his wife
transported him to an urgent care
facility where he was found to have
orthostatic hypotension. A diagnosis
of dehydration due to viral illness
was made and he was referred to
the emergency room for intravenous
fluid replacement, which was
administered without laboratory
306 w July/August 2009 w 106:4 Missouri Medicine
testing. On the fifth day of illness,
the dermatology clinic manager
determined a history of a tick bite
and suggested that he return to the
dermatology clinic. He presented
with symptoms of a severe headache,
photophobia, fatigue, and malaise
that the patient described as “feeling
awful.” There were no symptoms
of cough, diarrhea, or conjunctivitis,
and no history of contact with wild
animals. Temperature was 101.2º
F. There was no rash, no ulcer, and
no lymphadenopathy. A persistent
excoriated papule was present at the
site of the partially removed tick.
The remainder of the examination
was unremarkable. A diagnosis
of tick-borne febrile illness was
made. Further laboratory evaluation
included an acute complement
fixation titer for F. tularensis of <
1:20, immunofluorescent RMSF
IgG and IgM titers of < 1:64,
and negative Ehrlichia chaffeensis
antibodies (IgG < 1:64 and IgM
< 1:20). A two-week course of
doxycycline therapy 100 mg b.i.d.
was initiated. The night after this
therapy was begun, the patient
sweated profusely. The next day he
felt much better and was afebrile on
that day and subsequently. Three
weeks later, repeated RMSF and
Ehrlichia chaffeensis titers were
unchanged. A diagnosis of tularemia
was made when an F. tularensis
convalescent titer of 1:2560, a 128fold
rise, was obtained.
Case Three: Confirmed
Human Monocytic
Erlichosis
In July, 2008, a 77-year-old
female Crawford County resident
felt quite ill and saw her physician
with fever, malaise, and myalgia. She
subsequently described the severity
of the illness: “I have never been that
sick before and I don’t ever want to
be that sick again. I was sick for two
weeks. My head hurt. I hurt all over.
I had a fever for four days and I had
no appetite.” At presentation, the
patient recounted recent tick bites
and a four-day history of fever up to
102° F. Her white blood cell count
was 11.4 X 10³/μL (normal 4/0-10.5
X 10³/μL) and the platelet count was
159 X 10³/μL (normal 150-450 X
10³/μL). Hepatic transaminases
were elevated, with AST 142 (12-
32) and ALT 460 (8-46). The
hepatitis panel was all negative.
The indirect immunofluorescence
assay for IgG antibodies (IgG-IFA)
to Ehrlichia chaffeensis was < 1:20.
When repeated three weeks later,
the IgG-IFA to Ehrlichia chaffeensis
had risen to ≥1:1024, which along
with the clinical history of fever
and a headache, confirmed this case
of human monocytic ehrlichiosis
(See Table 1). The patient was
treated with a two-week course of
doxycycline, 100 mg b.i.d., rapidly
felt better, and recovered fully. The
next month, liver enzymes, white
blood cell and platelet counts were
all normal.
Discussion
All three cases illustrate the
nonspecific early presentations of
tick-borne febrile illnesses. Here
we give a brief review of early
presentations of these illnesses
and the issue of diagnostic delay
as it pertains to disease course and
response to therapy. In all three
illnesses, failure to give timely
therapy may result in a severe or even
fatal course.
In one recent series of RMSF

in children, delays in diagnosis were
found to be “unacceptably common,”
with fatality rates of 3% still observed
for this rickettsial illness. 2 In this
series, after a median duration of
illness of six days, only 5% of patients
had received specific anti-rickettsial
therapy. Tick bites were recalled
by only 49% of these patients.
Over 50% of children in this series
had only rash, fever, headache,
and nausea and/or vomiting as
symptoms. Kaufmann et. al. stated,
“the initial symptoms of RMSF are
nonspecific and include headache,
gastrointestinal disturbances, malaise,
and myalgias, followed by fever and
rash….The classic triad of fever,
rash, and history of tick exposure is
uncommon at presentation.” 3
Although our case could be
considered a “probable” case of
RMSF per the Missouri Department
of Health and Senior Services
website, as it was a was a “clinically
compatible case with supportive
laboratory evidence,” 1 the clinical
findings were more suggestive of
tularemia. As the single RMSF
titer of 1:128 was only supportive,
and no convalescent serology was
obtained, this case could not be
confirmed. This case illustrates a
problem frequently encountered in
documenting tick-borne illnesses--
the convalescent sera are often not
obtained. Approximately 30 cases
of clinically-compatible RMSF were
reported during 2007 and 2008 in
the Phelps and Maries County areas.
Unfortunately, these cases all lacked
convalescent serum samples, and
therefore a definitive diagnosis could
not be made.
The most rapid and specific
diagnostic assays for Rocky Mountain
spotted fever use molecular methods
such as polymerase chain reaction
(PCR) performed on fresh skin
biopsies. 4 PCR DNA techniques can
also be done on fixed tissues, but
with less sensitivity than on unfixed
tissues. PCR can detect DNA of only
5-10 R. rickettsiae organisms in a
tissue sample. The PCR procedure
is more specific than antibody-based
methods which are often only genus
or spotted fever group-specific. 4 The
RMSF PCR can be accomplished
with a small punch biopsy and
requires no follow-up test as do
serologic methods.
The second case illustrates
the severity of early symptoms of
tularemia. The most common
form of tularemia presents as an
ulceroglandular skin lesion, usually
at the site of a tick bite. The next
most common form is glandular, with
lymphadenopathy and no apparent
skin lesion. The other forms
of tularemia are oculoglandular,
pharygeal, intestinal, pneumonic
and typhoidal. 1 As gastrointestinal
symptoms were the predominant
localizing complaints, our case was
most compatible with early typhoidal
tularemia.
Delayed diagnosis and late
administration of effective antibiotic
therapy can result in increased
morbidity and mortality for
tularemia. Two of 11 tularemia
cases reported from Oklahoma
in 2001 were fatal. 5 The median
time to diagnosis was 18 days in
the nonfatal cases, but 45 days for
one of the two fatal cases (the time
to diagnosis was unknown for the
second fatal case, as the patient was
found comatose in his home). In
another tularemia series, 12 cases
of illness with a shorter, nonfatal
outcome, had treatment begun
earlier than 16 cases with a more
prolonged or relapsing course. 6
The only fatality in the series was
in this latter group of 16 cases with
treatment begun later. According to
the Missouri Department of Health,
Communicable Disease Investigation
Online Reference Manual, 1 tularemia
should be included in the differential
diagnosis of any patient in an area
where the disease is endemic who
has unexplained febrile illness and
exposure to ticks, biting flies, or
animal tissue. Patients may also be
infected by direct contact with wild
or domestic animals, including cats. 7
The third case illustrating
confirmed human monocytic
ehrlichiosis (herein called ehrlichiosis
as granulocytic ehrlichiosis is
not endemic in Missouri), is also
illustrative of a tick-borne illness
with relatively nonspecific flulike
symptoms at the onset. Both
Dumler et. al. and Roland et. al.
noted that ehrlichiosis generally
presents as undifferentiated fever. 8,9
Everett et. al. noted that fever, chills,
nausea, and headache were the
predominant symptoms. 10 Dysgeusia,
cough, pharyngitis, regional
lymphadenopathy, abdominal
tenderness, photophobia, myalgia
and back pain may occur in a
minority of cases. An accompanying
rash also occur in a minority of
cases, most commonly found in
children, usually in the form of a
diffuse erythema that is termed toxic
erythema. 10 Thrombocytopenia,
leukopenia, and increased serum
transaminase activity are helpful
laboratory features, 8,10 of which
only the elevated transminases were
present in of our case.
Prince et. al. noted that delaying
ehrlichiosis treatment while awaiting
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confirmatory tests is unnecessary,
and may result in a less favorable
patient outcome. 11 As Everett et
al. noted, response to doxycycline
is dramatic. 10 When treatment is
delayed, some patients can progress
to severe multisystem disease with
toxic shock-like syndrome. 11 The
case-fatality rate for ehrlichiosis
remains approximately 3%. 12
After serologic methods,
amplification of the ehrlichial DNA
by polymerase chain reaction (PCR)
is the next most frequently used
method for detecting ehrlichia
infection. 13 This test is available
from CDC through the Missouri
State Health Laboratory. E.
Chaffeensis DNA can be detected
by PCR from the blood of clinically
ill patients three to seven weeks
following the onset of symptoms. 13
Serologic studies for tick-borne
illnesses under consideration are
non-diagnostic within the first few
days of tick-borne illnesses. Therapy
should be instituted based solely on
clinical suspicion and/or findings,
and, if serological methods are used,
convalescent serology should be
obtained for confirmation 4 weeks
later.
Symptoms in all three cases
serve to illustrate the admonition
of Kaufmann et. al.: the initial
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manifestations of tick-borne diseases
are nonspecific 2 . None of the
three patients had a rash. Only
two reported tick bites initially, a
common finding which is sometimes
of limited diagnostic help in rural
Missouri. All cases occurred during
the peak incidence of these diseasesfrom
April to October. Especially in
springtime, diagnosis of these tickborne
illnesses is difficult, so these
severe illnesses must be kept within
the differential diagnosis. Severity
of symptoms, as in our cases, can
prompt further testing. If medical
practitioners will listen to the details
revealed by the patient or spouse,
especially when accompanied by
phrases such as “I’ve never been
that sick before,” and “he’s not a
complainer,” hopefully we will be
able to diagnose tick-borne illnesses
with nonspecific symptoms at an
earlier stage, thereby preventing
fatalities.
Acknowledgment
We thank the Office Manager
of the Dermatology Center of
Rolla, Karen Rosenburg, who was
responsible for the promptness of
medical attention in the second case.
References
1. http://www.dhss.mo.gov/CDManual/
CDManual.htm accessed January 18, 2009.
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Woods CR, Jackson MA, Patterson LE, Jacobs RF;
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Disclosure
None reported. MM