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Ehrlichia chaffeensis Seroprevalence Among Children in the Southeast and South-Central Regions of the United States
Gary S. Marshall, MD;
Richard F. Jacobs, MD;
Gordon E. Schutze, MD;
Helene Paxton, MS;
Steven C. Buckingham, MD;
John P. DeVincenzo, MD;
Mary Anne Jackson, MD;
Venusto H. San Joaquin, MD;
Steven M. Standaert, MD;
Charles R. Woods, MD;
for the Tick-Borne Infections in Children Study Group
Arch Pediatr Adolesc Med. 2002;156:166-170.
ABSTRACT
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Background The reported annual incidence of human monocytic ehrlichiosis, which
is due to infection with Ehrlichia chaffeensis, is
as high as 5.5 per million in some states, but serosurveys suggest much higher
infection rates in some populations.
Objective To estimate the prevalence of E chaffeensis
infection among children aged 1 to 17 years living in the southeast and south-central
United States.
Design Cross-sectional serosurvey.
Setting Seven academic pediatric medical centers in the southeastern and south-central
United States.
Patients Nineteen hundred ninety-nine children (approximately 300 at each center)
having their blood drawn for any reason.
Main Outcome Measure The presence of antibody at 2 different cutoff titers to E chaffeensis, as detected by indirect immunofluorescence assay.
Results Overall, 250 children (13%) had E chaffeensis
antibody titers of 1:80 or higher and 61 (3%) had titers of 1:160 or higher.
Age-adjusted seroprevalence rates varied widely between sites. At 1:80 or
higher, the highest rate was in Winston-Salem, NC (22%), and the lowest was
in Louisville, Ky (2%). At 1:160 or higher, the highest rate was in Kansas
City, Mo (9%), and the lowest was in Oklahoma City, Okla (<1%). In univariate
analyses, no associations were found between seroprevalence at either cutoff
value and sex, race, source of specimen, or residence demographics. However,
age was a significant predictor of seroprevalence at both cutoff values. In
multiple logistic regression analysis, study site and age remained strong
predictors of seroprevalence, but living in a nonurban ZIP code was not significantly
related.
Conclusion Infection with E chaffeensis, or related ehrlichiae,
may be more common in children than previously recognized.
INTRODUCTION
EHRLICHIAE ARE small, gram-negative, obligate intracellular coccobacilli
belonging to the family Rickettsiaceae. They infect circulating leukocytes,
where they divide into host membrane-bound clusters called morulae, which
are visible by light microscopy.1-2
The first case of human ehrlichiosis in the United States was reported in
1987 in a man who had received a tick bite in Arkansas.3
Initially thought to be due to Ehrlichia canis, an
established pathogen in dogs,4 this infection
was subsequently shown to be caused by a closely related species, now known
as Ehrlichia chaffeensis.5-6
This agent is the cause of human monocytic ehrlichiosis, which is distinguished
by a predominance of morulae in mononuclear cells. Amblyomma
americanum and Dermacentor variabilis have
been suggested as vectors, and deer are likely reservoirs.7
Descriptions of clinical illness, which are biased toward more severe
manifestations of disease, emphasize the occurrence of fever, headache, myalgia,
leukopenia, thrombocytopenia, anemia, and the elevation of hepatic transaminase
levels; rash is seen less commonly than in those with Rocky Mountain spotted
fever.8-9 The median duration
of illness is about 3 weeks, and the fatality rate is as high as 5%. Whereas
most reported disease is in older adults,8-9
ehrlichiosis has been reported in children,10-11
with recent reports12 emphasizing the occurrence
of severe life-threatening disease. Ehrlichiosis is almost certainly underrecognized.
The highest reported average annual statewide incidence rate for human monocytic
ehrlichiosis is only 5.5 cases per million (Arkansas).13
Despite reporting rates of this magnitude, several studies show ehrlichiosis
to be a relatively common cause of undifferentiated febrile illness in adults,
with14 and without15
a history of a tick bite. The occurrence of subclinical ehrlichiosis was underscored
in a study16 of a golf-oriented retirement
community in eastern Tennessee, which demonstrated serological evidence of
prior infection in 12.5% of residents, although few reported compatible illnesses.
Similarly, 4.6% of residents of a semirural subdivision in northern California
had antibodies to E chaffeensis but no recollection
of illness suggesting ehrlichiosis.17 Other
studies18 estimate the prevalence of prior
infection with ehrlichiae to be as high as 7% in selected populations.
Because Rocky Mountain spotted fever, which is transmitted by one of
the same tick vectors, is more common in children than in adults,19 it seems logical that exposures to ehrlichiae occur
in childhood. In addition, studies18, 20-22
show that infection with Rickettsia rickettsii, the
causative agent of Rocky Mountain spotted fever, is probably much more common
than disease incidence reports suggest. Despite this, to our knowledge, no
studies have looked specifically at the prevalence of ehrlichia antibodies
in children living in tick-endemic regions of the country.
PATIENTS AND METHODS
POPULATION SPECIFICATION AND SAMPLING
Seven sites located in the "tick belt" of the southeastern and south-central
United States participated in the study. From east to west, these sites were
as follows: Winston-Salem, NC; Louisville, Ky; Nashville, Tenn; Memphis, Tenn;
Little Rock, Ark; Kansas City, Mo; and Oklahoma City, Okla. Approximately
300 patients aged 1 to 17 years were studied at each site. Plasma or serum
specimens were obtained from residual volumes in the site's chemistry laboratory
after the appropriate clinical tests were performed. This method thus sampled
children with any diagnosis having blood drawn for any reason. Because specimens
were stripped of unique personal identifiers and were anonymously coded, the
need to obtain informed consent was waived by each institution's human studies
committee. Collections occurred between February 22, 1998, and July 24, 1998,
at all sites except Oklahoma City, where collections occurred between July
21, 1999, and September 27, 1999. Patient data recorded for each specimen
included the following: study site, date of birth, date of specimen collection,
source of specimen (hospital admission, emergency department visit, or other
outpatient visit), sex, race, and ZIP code of residence.
SEROLOGICAL TESTS
Specimens were tested in one laboratory (PanBio InDx, Inc, Baltimore,
Md) for antibodies to E chaffeensis by indirect immunofluorescence
assay (IFA). Vero cells infected with strain 91HE1723
were fixed onto glass slides containing 6-mm wells. Serum samples were diluted
1:80 in phosphate-buffered saline and reacted with antigen wells at room temperature
for 30 minutes. Slides were then washed with phosphate-buffered saline, rinsed
with deionized water, and air dried. Bound antibodies were detected using
a fluorescein isothiocyanate–conjugated polyclonal goat antiserum (diluted
1:100 in phosphate-buffered saline) reactive with human IgG, IgA, and IgM
(American Qualex, San Clemente, Calif). After 30 minutes at room temperature,
slides were rinsed with phosphate-buffered saline and counterstained with
eriochrome black. Blinded laboratory personnel examined the slides for bright
yellow bodies corresponding to intracytoplasmic morulae using epifluorescence
microscopy. Specimens that were positive for morulae at the screening dilution
of 1:80 were retested and diluted to determine the end point titer. All positive
serum samples were also tested for antibody to R rickettsii and Rickettsia typhi (Rickettsia IFA IgG
Test Kit [used according to the manufacturer's instructions]; MRL Diagnostics,
Cypress, Calif). Each assay included positive and negative controls. To control
for storage and handling, and to provide an assessment of signal detection,
6 control serum samples were sent to 6 of the sites for random inclusion in
their sequence of specimens (control serum samples were not available for
Kansas City). Two of these were positive for E chaffeensis antibody, 2 were positive for R rickettsii
antibody, and 2 were negative for antibodies to both organisms.
ANALYSIS
Data were stored and analyzed on a computer (Macintosh PowerBook G3;
Apple Computer, Inc) running a statistical analysis program (StatView 5.0;
SAS Institute Inc, Cary, NC). The 1998 Centers for Disease Control and Prevention
surveillance definition of probable ehrlichiosis24
included an IFA antibody titer of 1:64 or higher (the 2000 definition refers
only to cutoff values established by individual laboratories25).
However, cutoff values for positive IFA titers in published seroprevalence
studies16-18,22
of ehrlichiosis vary from 1:64 or higher to 1:80 or higher. Because standards
for interpretation of these assays in seroepidemiologic studies do not exist,
the present data were analyzed at a cutoff value of 1:80 or higher and at
a more stringent cutoff value of 1:160 or higher. For analysis, age was collapsed
into the following categories: 1 to 6, 7 to 12, and 13 to 17 years. Race was
dichotomized into white and nonwhite. Based on 1990 census data, ZIP codes
were demographically categorized as follows: (1) urban ( 75% of households
classified as urban [places of 2500 persons incorporated as cities, villages,
boroughs, and towns] or urbanized (places and their adjacent densely settled
surrounding territories [at least 1000 persons per 2.6 km2] that
together have a minimum of 50 000 persons); and (2) all others.26 Categorical associations between variables were sought
in univariate analyses using the  2 test; in all cases, expected
cell frequencies were greater than 5. Site-specific seroprevalence rates were
adjusted for differences in age distribution using the entire study population
as the reference. Multiple logistic regression was performed using 6 variables:
study site, age, source of specimen, residence, race, and sex. Variables that
were highly significant in univariate analyses were entered into the model
first, and for each variable, the element with the lowest seroprevalence rate
was used as the reference level. Significance for all analyses was defined
at an  level of .05.
RESULTS
DEMOGRAPHICS
A total of 1999 subjects (1015 male subjects) were studied, distributed
as follows: Kansas City, n = 194; Little Rock, n = 296; Oklahoma City, n =
296; Nashville, n = 299; Louisville, n = 300; Memphis, n = 302; and Winston-Salem,
n = 312. The overall age distribution is given in Table 1. Sites differed significantly for the age distribution of
the subjects (P<.001). For example, in Kansas
City, 40% of the subjects were aged 1 to 6 years and 27% were aged 13 to 17
years. By contrast, in Winston-Salem, 18% were aged 1 to 6 years and 46% were
aged 13 to 17 years. The sex proportion did not differ significantly between
sites (P = .07). However, sites differed significantly
in racial distribution and in the proportion of subjects living in an urban
setting (P<.001 for both). Most specimens (68%)
were obtained in the outpatient setting (14% at an emergency department visit
and 54% from other outpatient settings); the remainder were from children
admitted to the hospital. There were significant differences in the relative
proportions of these sources between sites (P<.001).
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Table 1. Age Distribution of the Study Subjects
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SEROLOGICAL RESULTS
Of the 12 randomly included positive control serum samples for E chaffeensis, 10 were correctly identified. All 12 R rickettsii control serum samples and all 12 negative
control serum samples were correctly identified as negative in the E chaffeensis IFA. Figure 1
gives the distribution of E chaffeensis titers in
the study population. Overall, 250 children (13%) had titers of 1:80 or higher;
of these children, only 6 also had antibody to R rickettsii at 1:64 or higher, and none had antibody to R typhi. Sixty-one children (3%) had ehrlichia titers of 1:160 or higher.
As seen in Figure 2, age-adjusted
seroprevalence rates varied widely between sites. At 1:80 or higher, the highest
rate was in Winston-Salem (22%) and the lowest was in Louisville (2%). At
1:160 or higher, the highest rate was in Kansas City (9%) and the lowest was
in Oklahoma City (<1%).
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Figure 1. Distribution of positive Ehrlichia chaffeensis titers. The percentage of total specimens (N
= 1999) is shown above the bars.
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Figure 2. Age-adjusted seroprevalence by
site at different cutoff values.
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OTHER PREDICTORS
In contingency table analyses, no univariate associations were found
between ehrlichia seroprevalence at either cutoff value and sex, race, source
of specimen, or residence demographics. Age group was a significant predictor
of seroprevalence at both cutoff values. At 1:80 or higher, the seroprevalence
was 8% in 1- to 6-year-old subjects, 12% in 7- to 12-year-old subjects, and
18% in 13- to 17-year-old subjects (P<.001). At
1:160 or higher, the seroprevalence was 1% in 1- to 6-year-old subjects, 3%
in 7- to 12-year-old subjects, and 5% in 13- to 17-year-old subjects (P<.001). Table 2
gives the results of multiple logistic regression analysis at both cutoff
values. Study site remained the strongest predictor of seroprevalence. At
1:80 or higher, the odds ratios ranged from 4.2 in Memphis to 15.0 in Winston-Salem
(with Louisville as the reference level), and were significant for all sites.
At 1:160 or higher, the odds ratios ranged from 1.8 in Memphis to 24.5 in
Kansas City (with Oklahoma City as the reference level), and were significant
for Nashville, Little Rock, Winston-Salem, and Kansas City. Age remained a
significant predictor of seroprevalence at both cutoff values, but only for
the 13- to 17-year-old group. The only other variable to achieve significance
in logistic regression was urban residence at the 1:80 or higher cutoff value
(P = .05).
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Table 2. Multiple Logistic Regression Analysis of Risk Factors for Ehrlichia chaffeensis Seropositivity
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COMMENT
Tickborne infections have gained public health importance as residential
growth has impinged on rural geographic areas and outdoor activities have
become more popular.27-28 Ehrlichiosis
is considered one of these emerging zoonoses.7
The present study shows a high prevalence of IFA antibodies reactive with E chaffeensis among children living in the southeast and
south-central United States. Even using a stringent cutoff value for positive
IFAs, the prevalence of antibody was as high as 9% at one site. The present
method does not exclude the possibility that antibodies to cross-reacting
ehrlichiae or rickettsiae were detected in some subjects.7, 22, 29
Nevertheless, the data suggest that childhood exposures to ehrlichiae are
much more common than would be expected from disease incidence reports. It
is possible that the antibodies detected herein were generated by infection
with related minimally pathogenic ehrlichia species. Alternatively, E chaffeensis infection in many children may be subclinical,
and the higher reported prevalence of disease in adults may relate to host
factors that increase severity.30 The spectrum
of disease may also be broader than previously thought, and symptoms such
as fever, headache, malaise, myalgia, anorexia, and rash could be mistaken
for self-limited viral syndromes. If such is the case, recognizing and treating
mild or early cases might be important in preventing more severe manifestations
of disease in some individuals.
The intended sample herein was consecutive children having their blood
drawn at each center. The actual sample, however, included only those children
with sufficient serum available after clinical tests were performed. This
may explain why the age distribution was shifted toward older subjects (Table 1); older subjects may have had more
blood obtained and, thus, more was left over for this study. Because many
children at all ages were included, it is unlikely this sampling bias affected
the results.
The present study was not population based, and the serological methods
did not differentiate incident from prevalent infection. Conceivably, some
children had their blood drawn because of symptoms suggesting rickettsial
infection, although 82% of the serum specimens were collected between February
and May, when tickborne diseases are less common. However, because clinical
data were not obtained, incident infection cannot be excluded. It is also
possible that this study underestimated the true prevalence of ehrlichiosis,
because declining antibody titers have been observed after acute infection.29
Other biases may have been operative in this convenience sample. For
example, children presenting to these regional centers may have been triaged
from rural areas, where tick exposures are expected to be more common. On
the other hand, hospital admissions might have overrepresented children with
chronic conditions that limit mobility and, thus, tick exposure. Alternatively,
children with long-term sequelae of ehrlichiosis (eg, neurological damage)
might be overrepresented in a hospital-based sample. Emergency department
visits might have overrepresented urban children, who are expected to have
fewer tick exposures. The impact of these biases, which had competing directions,
was minimized in the analysis.
The finding of increasing seroprevalence with age was expected based
on the accumulation of exposures over time, and affords internal consistency
to the study. The low seroprevalence rate in Louisville was consistent with
a low annual reporting rate for disease in Kentucky (0.40 cases per million).13 The corresponding statewide reporting rates per million
for other sites were 5.53 in Arkansas (Little Rock), 4.72 in North Carolina
(Winston-Salem), 3.05 in Missouri (Kansas City), and 2.90 in Oklahoma (Oklahoma
City).13 Data were not available for Tennessee
(Memphis and Nashville). The most unexpected finding in this study was the
lack of a strong relationship between nonurban residence and seropositivity.
This may have been an artifact of the method used to classify ZIP codes of
residence. Some ZIP codes classified as urban in 1990 may have been rural
before that. Older children living in those areas may have been more exposed
to ticks when they were young, and might carry markers of previous ehrlichia
infection despite currently residing in an urban area. Alternatively, living
in an urbanized area does not preclude travel to wooded areas. In addition,
urbanization per se may not be as important a factor as the local density
of foliage and the regional concentration of animal reservoirs. Along these
lines, there are reports31-32
of urban outbreaks of rickettsial diseases and isolated hyperendemic foci.
The data presented herein suggest that infection with E chaffeensis or related ehrlichiae is more common in children than
would be expected from disease incidence reports. Active population-based
surveillance studies are warranted.
| What This Study Adds
The reported annual incidence of human monocytic ehrlichiosis is low,
but serosurveys suggest high infection rates in selected populations. Because
children are often exposed to ticks, this study investigated the prevalence
of antibody to E chaffeensis among children living
in endemic regions of the United States.
Overall, 13% of the children had antibody titers of 1:80 or higher and
3% had titers of 1:160 or higher. Age-adjusted seroprevalence rates using
the stringent cutoff value were as high as 9% in some areas. Infection with E chaffeensis may be more common in children than previously
recognized.
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AUTHOR INFORMATION
Accepted for publication September 23, 2001.
This study was supported by grant 97-44 from the Alliant Community Trust
Fund, Louisville, Ky.
The Tick-Borne Infections in Children Study
Group
University of Louisville, Louisville, Ky: Gary
S. Marshall, MD, Gordon G. Stout, BS. PanBio InDx, Inc,
Baltimore, Md: Helene Paxton, MS, Joan Antony, BS. Vanderbilt University School of Medicine, Nashville, Tenn: Steven M.
Standaert, MD, Michael Leonard, MD. The Johns Hopkins University
School of Medicine, Baltimore: J. Stephen Dumler, MD. University of Arkansas for Medical Sciences, Little Rock: Richard F.
Jacobs, MD, Gordon E. Schutze, MD. University of Tennessee
Health Sciences Center, Memphis: Steven C. Buckingham, MD, John P.
DeVincenzo, MD. University of Missouri, Kansas City:
Mary Anne Jackson, MD. University of Oklahoma Health Sciences
Center, Oklahoma City: Venusto H. San Joaquin, MD. Wake Forest University School of Medicine, Winston-Salem, NC: Charles
R. Woods, MD.
Corresponding author and reprints: Gary S. Marshall, MD, Division
of Pediatric Infectious Diseases, University of Louisville School of Medicine,
571 S Floyd St, Suite 321, Louisville, KY 40202 (e-mail: gsmars01{at}athena.louisville.edu).
From the Divisions of Pediatric Infectious Diseases, University of
Louisville School of Medicine, Louisville, Ky (Dr Marshall), and the University
of Arkansas for Medical Sciences, Little Rock (Drs Jacobs and Schutze); PanBio
InDx, Inc, Baltimore, Md (Ms Paxton); the Divisions of Pediatric Infectious
Diseases, University of Tennessee Health Sciences Center, Memphis (Drs Buckingham
and DeVincenzo), the University of Missouri, Kansas City (Dr Jackson), and
the University of Oklahoma Health Sciences Center, Oklahoma City (Dr San Joaquin);
Department of Preventive Medicine, Vanderbilt University School of Medicine,
Nashville, Tenn (Dr Standaert); and Division of Pediatric Infectious Diseases,
Wake Forest University School of Medicine, Winston-Salem, NC (Dr Woods).
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