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Journal of Clinical Microbiology, February 2000, p. 635-638, Vol. 38, No. 2
Department of
Pathology,1 Department of Medicine,
Division of Infectious Diseases,2 and
Department of Biochemistry and Molecular
Biology,3 New York Medical College, Westchester
Medical Center, Valhalla, New York, and Department of
Pathology, Johns Hopkins Medical Institutions, Baltimore,
Maryland4
Received 16 August 1999/Returned for modification 8 October
1999/Accepted 23 November 1999
We evaluated the antibody responses in the sera of 24 patients with
culture-confirmed human granulocytic ehrlichiosis (HGE). Antibody
titers were measured by an indirect immunofluorescent-antibody assay
(IFA) by using a local human isolate as the source of antigen. All
patients received appropriate antimicrobial treatment. One hundred five
serum specimens collected at baseline and at periodic intervals for up
to 14 months were included in the study. Seroconversion was observed in
21 of 23 patients (91.3%) from whom convalescent-phase sera were
obtained. Antibodies were first detected at an average of 11.5 days
after onset of symptoms. Peak titers ( Human granulocytic ehrlichiosis
(HGE) is an emerging vector-borne infectious disease transmitted
through the bite of infected Ixodes ticks
(14). Most cases to date have been reported from the Midwest
and Northeast United States, where Ixodes scapularis ticks
are highly prevalent (1, 3, 4, 16). Classically, patients
with HGE present with high fever and constitutional signs and symptoms
a few days following a tick bite (1, 3).
Routine laboratory tests show leukopenia and/or thrombocytopenia and
elevation of liver enzyme levels (1, 3, 4). Specific tests
used to confirm the diagnosis during the acute phase include
microscopic detection of inclusions in peripheral blood granulocytes,
PCR with whole blood, and culture of the agent from blood (1, 3,
4, 6).
Detection of antibodies has also been used to support the clinical
diagnosis by using either human isolates or the closely related
ehrlichial species Ehrlichia equi as the source of antigen (5, 11, 12). Results of most serologic studies, however, have been based on clinically defined patient populations or a small
number of patients with culture-confirmed HGE (10, 12, 15).
The present study reports on the serologic test results for 24 patients
with culture-confirmed HGE, the largest cohort of patients with
culture-confirmed HGE tested to date, obtained by using a local human
isolate as the source of antigen in an indirect
immunofluorescent-antibody assay (IFA). A total of 105 serum specimens
collected at baseline and for up to 14 months after onset of symptoms
were studied. A comparison of the serologic findings obtained with a
Wisconsin human HGE isolate or E. equi as the antigen is
also presented.
(This study was presented in part at the 38th Interscience Conference
on Antimicrobial Agents and Chemotherapy, San Diego, Calif., 24 to 27 September 1998.)
Patients.
Twenty-four patients diagnosed with HGE by culture
of the HGE agent from blood were included in the study. These patients were diagnosed with HGE at the Westchester Medical Center, Valhalla, N.Y., between 1995 and 1998. All patients were treated with doxycycline within 8 days of the initial visit. The clinical and laboratory features of 11 of these patients have been reported previously (7-9, 13).
Sera.
A total of 105 serum specimens collected during the
first visit and at different time intervals for up to 14 months after onset of symptoms were tested. Sera were frozen at IFA.
A local HGE isolate designated NY-13, which was
cultured in HL-60 cells as described previously (6), was the
source of antigen. The isolation and identification of this organism
were published previously (8). This isolate was chosen as
the source of antigen because it was the first one to be maintained in
continuous culture in our laboratory. Slides were prepared for IFA when
>90% of the HL-60 cells were infected, as evidenced by the presence of intracellular inclusions after Wright staining. A suspension of
approximately 5 × 103 infected cells was applied to
each well of 12-well Teflon-coated slides (Cell Line; Erie Scientific
Co., Portsmouth, N.H.), air dried, and fixed in acetone for 10 min.
Prepared slides were stored at Patients.
Selected characteristics of the 24 patients included
in this study are shown in Table 1. There
were 14 males with ages ranging from 20 to 74 years (median age, 47.5 years) and 10 females ranging in age from 1 week to 80 years (median
age, 53 years). The patients presented at an average of 6.2 days after
onset of symptoms. Five of these patients had concomitant Lyme
borreliosis with erythema migrans, with the Lyme borreliosis in four
patients confirmed by isolation of Borrelia burgdorferi from
the skin lesion. Data for three of the coinfected patients were
reported previously (7, 8, 13).
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Serology of Culture-Confirmed Cases of Human Granulocytic
Ehrlichiosis
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
2,560 for 71.4% of patients
and 640 for 95.2% of patients) were obtained an average of 14.7 days
after onset of symptoms. Eleven of 13 patients (84.6%) from whom sera
were collected between 6 and 10 months after onset of symptoms were
still seropositive, and sera from 5 of 10 (50%) patients tested
positive between 11 and 14 months after onset of symptoms. For a subset
of 71 serum specimens from 17 patients with culture-confirmed HGE also
tested by IFA by using either a human isolate from Wisconsin or an
Ehrlichia equi isolate from a horse, there was qualitative
agreement for 62 serum specimens (87.3%). Peak titers were higher,
however, with the local human HGE isolate, but the difference was not
statistically significant. In summary, most patients with
culture-confirmed HGE develop antibodies within 2 weeks of onset of
symptoms. Antibodies reach high titers during the first month and
remain detectable in about one-half of patients at 1 year after onset
of symptoms.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
70°C if they were not tested within a few weeks of collection. All sera
obtained from an individual patient were tested simultaneously.
70°C until they were used. To
maintain the consistency of the antigen preparations, several hundred
slides were prepared at the same time with low-passage-number (less
than five passages) NY-13 isolates. Positive and negative controls were
included on each slide. Slides with E. equi-infected horse
neutrophils (MRK isolate cultured from a horse in California) or HL-60
cells infected with the Webster HGE isolate from Wisconsin were
prepared as described previously (5) and were tested at the
Johns Hopkins Medical Institutions by J.S.D. Serum specimens were
tested in both laboratories (New York Medical College and Johns
Hopkins) at an initial dilution of 1:80 in phosphate-buffered saline
containing 0.5% of nonfat dry milk (PBSM). Bound antibodies were
detected after incubation with fluorescein isothiocyanate-labeled goat
anti-human immunoglobulin G (IgG), IgM, and IgA (Kirkegaard & Perry
Laboratories, Gaithersburg, Md.) diluted 1/50 in PBSM. Specimens
showing fluorescent intracellular inclusions at a dilution of 1:80 were
considered reactive and were serially diluted up to 1:2,560 and tested
by IFA to determine the titer (5, 17). Specimens with titers
of 2,560 were considered to have a titer of 2,560 for the purpose of
analysis. For calculation of geometric mean titers (GMTs), titers of
<80 were given an arbitrary value of 40.
RESULTS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
TABLE 1.
Characteristics of the serology of 24 patients with
culture-confirmed HGE
Acute-phase serology. Eight of 21 evaluable patients (38%) tested positive for antibodies to the HGE agent at the first visit. The mean and median durations of disease prior to treatment for those with positive baseline serologies were 6.6 and 7 days, respectively, whereas they were 6.3 and 4 days, respectively, for the group of patients who tested negative at this visit (P = 0.53 for the comparison of medians; Mann-Whitney rank sum test). One patient who tested positive at baseline (patient 7, Table 1) had a prior episode of HGE that had been confirmed by PCR and serology 2 years earlier. Data for this patient were reported previously (8).
Serology in relation to disease duration. To assess the evolution of the antibody response, serum specimens obtained at baseline and thereafter were arbitrarily categorized into the following time intervals after onset of symptoms: <7 days, 7 to 14 days, 15 days to 1 month, 2 to 5 months, 6 to 10 months, and 11 to 14 months. For all but one patient at least one specimen was collected during the first month after onset of symptoms. For 5 of 23 patients (21.7%) two specimens were collected, and for 13 of 23 patients (56.5%) three specimens were collected within the first month after onset of symptoms. Twenty-one of 23 patients (91.3%) who provided specimens after they provided the baseline specimen developed antibodies (seroconverted), as determined by IFA. One of the patients who did not seroconvert was treated within 1 day of onset of symptoms (patient 23). The other patient who did not seroconvert presented 32 days after onset of symptoms and also tested negative by PCR and microscopy during the acute phase (patient 6).
Antibodies were first detected an average of 11.5 days (range, 1 to 36 days) following onset of symptoms with a GMT of 780 (Table 1). Peak titers of640 were obtained for 20 of 21 (95.2%) patients who
developed antibodies in the convalescent phase, and 15 of 21 (71.4%)
had peak titers of 2,560. Peak titers were first obtained an average
of 14.7 days after onset of symptoms (range, 7 days to 4 months).
Duration of antibodies.
Twenty of 22 (90.9%) specimens
collected between 2 and 5 months after onset of illness tested positive
by IFA. Antibodies to the HGE agent were detected by IFA (titers 80)
by 6 to 10 months for 11 of 13 patients (84.6%) and by 11 to 14 months
for 5 of 10 patients (50%) (Table 2).
The GMT increased to 964 between 2 and 4 weeks after onset of symptoms
and gradually declined over the next few months. By 11 to 14 months
after antimicrobial therapy the GMT was 130, with titers ranging from
<80 to 2,560.
|
Comparison of different antigen preparations for detection of
antibodies to HGE agent by IFA.
Seventy-one serum specimens from
17 patients with culture-confirmed HGE were also tested by IFA with
E. equi MRK-infected neutrophils or the Webster HGE isolate.
Forty-four of the 71 specimens obtained from eight patients were tested
with E. equi-infected neutrophils, and 27 specimens from
nine patients were tested with the Webster HGE isolate. Concordant
positive or negative results were obtained for 62 of 71 specimens
(87.3%). Discrepant results were obtained for three baseline and six
convalescent-phase specimens (Table 3).
Two of the baseline specimens were found to be positive only with the
Webster isolate, and one of the baseline specimens was found to be
positive only with the NY-13 isolate. When the IFA results obtained
with the NY-13 isolate were compared with the results obtained with the
MRK isolate, titers of 2,560 were obtained for six of seven patients
(85.7%) who seroconverted when the NY-13 isolate was used and for four
of seven patients (57.1%) when the MRK isolate was used. Similarly,
when the results obtained with the NY-13 and the Webster isolates were
compared, peak titers of 2,560 were obtained for four of six patients
(66.6%) in the convalescent phase when the NY-13 isolate was used and
for three of six patients in the convalescent phase (50%) when the
Webster isolate was used. The GMT of the peak titers was higher for
tests with the NY-13 isolate than for tests with the MRK isolate (2,317 versus 1,279; P = 0.172, paired t test)
or the Webster isolate (2,031 versus 1,140; P = 0.317,
paired t test).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
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The antibody response to the HGE agent was evaluated by IFA for a
cohort of 24 treated patients with culture-confirmed HGE. Twenty-one of
23 patients (91.2%) developed detectable antibodies (titers 80).
Antibodies were first detected an average of 11.5 days after onset of
symptoms (range, 1 to 36 days), with peak titers of 640 achieved
within 4 weeks after onset of symptoms. Ravyn et al. (15)
published a report on the use of IFA with culture-derived human
isolates from Minnesota for five patients with culture-confirmed HGE.
In that study they tested a few convalescent-phase specimens by
separate IgG- and IgM-specific IFA assays and obtained titers lower
than those that we found in our study (15). For two of their
five patients the highest IgG or IgM titer was 160. Unfortunately, due
to technical variables inherent to IFA, it is difficult to standardize
titer cutoff values. Differences in antigen sources and preparations,
use of polyvalent or monovalent fluorescent conjugates, and variability
in reading of the reactivity under a fluorescent microscope may account
for titer differences among laboratories (17).
There is no current consensus on the appropriate use of serology for the diagnosis of HGE. Screening serum dilutions range from 1:40 to 1:80, and many assays detect IgG selectively. When serum specimens collected early in convalescence are tested, it seems appropriate to use conjugates that detect both IgG and IgM antibodies. The findings of Ravyn et al. (15), as well as those of IJdo et al. (10) and Walls et al. (17) and our own findings (unpublished data), seem to indicate that IgM reactivity develops early in the antibody response to the HGE agent.
On the basis of our results, if only a single blood specimen is
available, it would seem appropriate to consider a titer of 640 rather
than a titer of 80 by a polyvalent IFA that detects both IgG and IgM
antibodies to support the diagnosis of a recent infection with the HGE
agent. Whether a titer of 80 is an appropriate cutoff for
seropositivity will require further study of control groups without
evidence of HGE. As for other infectious diseases, patients who develop
high titers of antibodies in the acute phase may remain seropositive
with gradually declining titers for long periods of time. Such patients
may have titers to HGE of 640 without indicating a recent infection. In
our cohort, 6 of 13 patients (46%) and 2 of 10 patients (20%) had
titers of 640 by 6 months and 1 year after onset of illness,
respectively. Furthermore, approximately one-half of our patients still
had antibody reactivity (titer 80) 1 year after treatment for HGE
infection; this is similar to the observations of Bakken et al.
(4) on the basis of testing for antibody to E. equi in patients from the Midwest (11 of 24 patients had
antibodies at 1 year after onset of symptoms).
In this study we also studied geographically unrelated isolates as a source of antigens, such as the Webster isolate of HGE from Wisconsin and the MRK isolate of E. equi cultured in California. Discrepant results were found for 9 of 71 (12.7%) serum specimens. Earlier detection of antibodies was found for two serum specimens when the Webster isolate was used and for one serum sample when the NY-13 isolate was used. Persistence of seropositivity was most frequent when the NY-13 isolate was used as the source of antigen. These differences might be due to technical factors. However, antigenic differences among HGE isolates do exist and might also account for variations in serologic assay results (2, 12, 17, 18). Preliminary studies in our laboratory have shown that the NY-13 isolate contains an immunodominant antigen of about 44 kDa which is also exhibited by other isolates of HGE (J. Knowles, K. Barber, B. Menefee, A. Markovits, G. Wormser, and M. Aguero-Rosenfeld, Abstr. VIII Int. Conf. Lyme Borreliosis and Other Emerging Tick-Borne Diseases, abstr. P255, p. 69, 1999). When choosing a particular isolate as a source of antigen, it would be prudent to validate its reactivity with sera from different geographic areas.
Although most patients in our series seroconverted, two did not develop detectable antibodies. One of these patients (patient 23) received antimicrobial treatment within 1 day of onset of symptoms. Prompt treatment of this patient may have aborted the development of antibodies. Two other patients who received antimicrobial therapy within 1 day of onset of symptoms, however, did develop antibodies. It is unlikely that the reason for the lack of detectable antibodies was the antigen source since those patients were also found to be negative by use of the other isolates of Ehrlichia used in this study. Furthermore, they were also found to be negative when their sera were tested against several other local human isolates (data not shown).
Enzyme immunoassays such as enzyme-linked immunosorbent assays or immunoblot assays are feasible alternatives to IFA for detection of antibodies to the HGE agent (15). Technical difficulties in reproducing the IFA and reading of the IFA results will stimulate the development of assays that use purified antigens. Zhi et al. (19) recently published a report on the cloning and expression of the 44-kDa immunodominant outer membrane protein of the HGE agent. Whether this cloned antigen is broadly cross-reactive among patients infected with different strains of HGE is unknown. In the meantime, IFA of an acute-phase serum sample plus a convalescent-phase serum sample collected 2 to 4 weeks after onset of symptoms is a sensitive test for confirmation of the diagnosis of HGE.
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ACKNOWLEDGMENTS |
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This work was supported by grant HLT-27018 from the Westchester County Department of Health to M.E.A.-R. and by grant RO1-AI41213 from the National Institute of Allergy and Infectious Diseases to J.S.D.
We thank Diane Holmgren, Susan Bittker, Denise Cooper, John Nowakowski, and Robert Nadelman, who helped to care for the patients included in this study, and Jennifer Walls, who assisted with serologic tests at Johns Hopkins University.
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FOOTNOTES |
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* Corresponding author. Mailing address: Clinical Laboratories Room 1J-11a, Westchester Medical Center, Valhalla, NY 10505. Phone: (914) 493-7389. Fax: (914) 493-5742. E-mail: maria_aguero-rosenfeld{at}nymc.edu.
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Journal of Clinical Microbiology, February 2000, p. 635-638, Vol. 38, No. 2
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Copyright © 2000, American Society for Microbiology. All rights reserved.
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