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Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3962-3966
Clinical Value of Soluble IgG Fc Receptor Type III in Plasma From
Patients With Chronic Idiopathic Neutropenia
By
Harry R. Koene,
Masja de Haas,
Marion Kleijer,
Tom W.J. Huizinga,
Dirk Roos, and
Albert E.G.Kr. von dem Borne
From the Central Laboratory of the Netherlands Red Cross Blood
Transfusion Service and Laboratory for Experimental and Clinical
Immunology, and Department of Hematology, Academic Medical Centre,
University of Amsterdam, Amsterdam, The Netherlands; and the Department
of Rheumatology, University Hospital Leiden, Leiden, The
Netherlands.
 |
ABSTRACT |
Previous studies have shown that the plasma level of soluble IgG Fc
receptor type III (sFc RIII) is a measure of the total body
neutrophil mass. The aim of this study was to determine whether the
plasma level sFcRIII is associated with the risk of contracting bacterial infections in patients with neutropenia. We collected blood
from 66 patients suffering from acquired idiopathic neutropenia, whose
blood was sent to our laboratory for diagnostic evaluation of
neutropenia (neutrophil count <1,500 cells/µL). Soluble FcRIII levels were measured in plasma. Genotype distibutions of FcR polymorphisms were determined. Clinical data were obtained from the
patient files. Patients were assessed as to whether or not they had
suffered from a bacterial infection 3 months before to 3 months after a
single sFcRIII measurement. In addition, longitudinal data were
obtained from 21 patients. Of the 66 neutropenic patients who were
included, 15 had suffered from a bacterial infection in the period 3 months before to 3 months after sFcRIII measurement. The age and sex
distribution was equal among the groups with and without infections, as
were the genotype frequencies of neutrophil FcR polymorphisms. Both
neutrophil count and plasma level sFcRIII were significantly lower
in the patient group with infections, compared with the noninfected
group (P = .03 and P < .0001, respectively). No
infections were reported for patients who had plasma sFcRIII levels
above 100 arbitrary units (AU; normal value, 30 to 200). After matching each infected patient with two noninfected patients having the same neutrophil count, sFcRIII plasma levels remained significantly lower in the group with infections (P = .0001). For the patients who were followed in time, no infections were reported
when sFcRIII levels were above 100 AU. In conclusion, our population
of patients with chronic idiopathic neutropenia with plasma sFcRIII
levels above 100 AU did not show an increased risk of contracting
bacterial infections.
| |
INTRODUCTION |
NEUTROPHILIC GRANULOCYTES play an
important role in the host defence against bacteria. Qualitative, as
well as quantitative, neutrophil disorders increase the risk of
contracting bacterial infections. Normally, the majority of body
neutrophils is in the bone marrow storage pool, whereas circulating
neutrophils comprise less than 5% of the total body amount of
neutrophils. Nevertheless, it is well established that a low number of
circulating neutrophils is correlated with an increased infection risk.
Prophylactic treatment with antibiotics or with granulocyte
colony-stimulating factor (G-CSF) is common practice in neutropenic
patients, especially in case of severe neutropenia (<500/µL).
Because not all neutropenic patients will contract a bacterial
infection, prophylactic therapy is not always necessary. Therefore, a
parameter that would allow a more adequate treatment indication would
be welcome. Human neutrophils express two different IgG Fc receptors
(FcR) on their cytoplasmic membrane, both of which bind IgG
complexes (reviewed in De Haas et al1). These receptors
play a crucial role in the process that leads to the degradation of
IgG-opsonized particles. Each neutrophil carries 10,000 to 30,000 copies of FcRIIa (CD32) and 100,000 to 300,000 copies of FcRIIIb
(CD16). Genetic polymorphisms on both FcRIIIb and FcRIIa
influence the receptor-ligand interaction.2-5
Soluble (s) FcRIII is present in plasma and other body fluids and is
mainly derived from neutrophils.6-8 Previous data suggest that the level of sFcRIII might be an additional parameter in the
evaluation of quantitative neutrophil disorders. The concentration of
sFcRIII in plasma correlates with the production of neutrophils in
the bone marrow.9,10 Depletion of the storage or
marginating neutrophil pool does not affect plasma sFcRIII levels,
whereas changes in bone marrow neutrophil production are followed by
changes in plasma sFcRIII levels after a few days.9,10
Neutrophils release FcRIIIb during apoptosis in vitro.11
In vivo, the lag time between changes in number of circulating
neutrophils and levels of sFcRIII suggests that plasma sFcRIII
originates from apoptotic tissue neutrophils and that neutrophils have
a tissue phase of approximately 6 days. From these data, we
hypothesized that the level of sFcRIII in plasma of neutropenic
patients could be used as an additional parameter to determine the
total body neutrophil mass and thus the infection risk in these
patients.
| |
MATERIALS AND METHODS |
Patients.
EDTA-anticoagulated blood was sent to the Central Laboratory of the
Netherlands Red Cross Blood Transfusion Service (CLB) for
diagnostic screening for the presence of neutrophil (auto)antibodies. Sixty-six consecutive adult patients (aged >18 years) with chronic (ie,  6 months) acquired idiopathic neutropenia were included from a
total of approximately 300 diagnostic requests. Informed consent and
clinical information was obtained via the treating physicians.
Neutropenia was defined as an absolute neutrophil count (ANC) below
1,500/µL. No autoantibodies were detected in the direct
immunofluorescence test. Patients were excluded when (1) the direct
immunofluorescence test was positive, ie, the neutropenia was
(auto)immune-mediated, (2) another autoimmune disease or an immunodeficiency apart from neutropenia was present, or (3) the neutropenia was drug-induced. The patients were evaluated as to whether
or not they had suffered from one or more bacterial infections in the
period 3 months before until 3 months after analysis. Bacterial infections were scored on the basis of a positive bacterial culture result, in addition to clinical symptoms. None of the patients received
prophylactic therapy. Twenty-one patients were followed in time.
Cell separation.
Blood from healthy controls or patients was centrifuged over a
Ficoll-Hypaque gradient (Pharmacia Fine Chemicals, Uppsala, Sweden)
with a specific gravity of 1.076 g/mL. Peripheral blood mononuclear
cells (PBMC) were harvested from the interphase for DNA isolation.
Erythrocytes in the pellet were lysed with isotonic NH4Cl
at 4°C. The remaining cells were >95% neutrophils.
Soluble FcRIII enzyme-linked immunosorbent assay (ELISA).
Levels of sFcRIII in (EDTA-) plasma or serum were
measured essentially as previously described.12 Briefly,
ELISA plates (Nunc Immunoplate Maxisorp, Rockslide, Denmark) were
coated with 5 µg/mL CD16 monoclonal antibody (MoAb) CLBFcRgran1 in
0.1 mol/L NaHCO3, pH 9.6. Unbound sites were blocked with
phosphate-buffered saline (PBS) containing 2% (vol/vol) milk
(PBS/milk). Patient plasma samples were diluted in high performance
ELISA (HPE) buffer (CLB, Amsterdam, The Netherlands). After washing the
plates with PBS containing 0.02% Tween-20 (vol/vol), the wells were
incubated with 25-fold and 50-fold dilutions of plasma or serum samples at room temperature in duplicate. The plates were then incubated for 1 hour with appropriate concentrations of a biotin-labeled polyclonal
antipan-FcRIII antibody, diluted in HPE buffer. After 30 minutes of
incubation with horseradish peroxidase-labeled streptavidin, diluted in
PBS/milk, 100 µL of substrate buffer was added. The colorimetric
reaction was stopped by addition of 2 mol/L
H2SO4, and the absorbance at 450 nm was
measured in a Titertek multiscan ELISA reader (Flow Laboratory,
Rockville, MD). Pooled plasma of 90 healthy individuals was used to
obtain a calibration curve. The concentration of sFcRIII in this
pool was set at 100 arbitrary units (AU; approximately 5 nmol/L; normal
range, 30 to 200 AU; approximately 1.5 to 10 nmol/L).12
Neutrophil FcRIIIb-neutrophil antigen (NA)
phenotyping.
Neutrophils were phenotyped with NA1- and NA2-specific MoAbs by an
indirect immunofluorescence test as described previously.13 Briefly, neutrophils were incubated with MoAb for 30 minutes at room
temperature and subsequently stained with fluorescein isothiocyanate (FITC)-labeled goat antimouse Ig. Binding of MoAbs was assessed by
fluorescence microscopy. When the amount of isolated neutrophils was
too small to perform phenotyping, genomic DNA was isolated from PBMC of
the patient, and the genotype was determined by polymerase chain
reaction (PCR). Previous work has shown that NA-genotyping and
NA-phenotyping results are in complete concordance.14
Neutrophil FcRIIIB and FcRIIA genotyping.
Genotyping for the NA system on FcRIIIb was performed as previously
described, based on two PCR-based allele-specific primer annealing
(ASPA) assays.14 A new PCR-based allele-specific
restriction analysis (ASRA) was developed to type for the
FcRIIA-131H/R polymorphism. Briefly, two
FcRIIA-specific primers were used to amplify a 77-bp fragment (sense: 5 -CAA GCC TCT GGT CAA GGT C-3;
antisense: 5-TGG AGA AGG TGG GAT CCA TA-3). The antisense
primer introduced an NdeI restriction site only in
FcRIIA-131H. The amplified FcRIIA-specific fragment was digested with restriction endonuclease NdeI after which fragments were electrophoresed in polyacrylamide gels and visualized with ethidium bromide and UV light. The
FcRIIA-131R/H gene frequencies in a healthy Caucasian
population (n = 93) were equal to the published ones.2
Statistical analysis.
GraphPad Instat (GraphPad Software, San Diego, CA) was used for
statistical calculations. After initial analysis of all the included
patients, each patient with an infection was matched with two patients
without infections who had an equal ANC to correct for any effect of
the neutrophil count on the infection incidence. Data were analyzed
with Student's t test. When differences in standard deviations
were significant, Welch's approximate t-test was used. FcR
genotype and phenotype distributions were compared with the
 2 test. A two-sided P value below .05 was
considered significant. When comparing the test characteristics of the
ANC and the plasma sFcRIII level, receiver operating characteristics
(ROC, ie, sensitivity v 1-specificity) curves were used to
determine the optimal cut-off point of the ANC.
| |
RESULTS |
Sixty-six patients with neutropenia of unknown origin were divided in
two groups who either did or did not suffer from a bacterial infection
in the period 3 months before to 3 months after sFcRIII measurement.
Table 1 shows the clinical and phenotypical
data of all included patients. Fifteen patients suffered from a
bacterial infection in the study period, as determined on the basis of
the clinical picture and a positive culture. Among the diagnosed
infections were recurrent upper respiratory tract infections (n = 4),
pneumonia (n = 3), urinary tract infections (n = 3, one urosepsis),
recurrent skin infections (n = 2), aphtous mouth ulcers (n = 2), and
infections of the gastrointestinal tract (n = 1). All infections were
treated successfully with antibiotics. As shown in Table 1, no
significant differences were observed regarding sex and age
distribution among the two groups. Fifty-three patients were typed for
the FcRIIa-131R/H and the FcRIIIb-NA(1,2) polymorphism. No
genomic DNA was available from 13 patients. The
FcRIIA and FcRIIIB genotype frequencies in the
infected and noninfected groups were not significantly different and
did not differ from frequencies in the normal (Dutch) population.15 No differences were observed in sex and age
between neutropenic patients with and without a bacterial infection 3 months before or after the sFcRIII measurement. The sFcRIII levels were significantly lower in the patients with infections compared with the patients without infections (49 ± 26 AU v
109 ± 66 AU, respectively; Welch's approximate t-test;
P < .0001). As shown in Table 1, the results of diagnostic
bone marrow examinations were essentially the same in the two groups.
The ratios between mitotic and postmitotic cells of the neutrophilic
lineage were not available. Like the sFcRIII levels, the mean number
of circulating neutrophils was significantly lower in the patients with
infections, compared with the patients without infections (860 ± 477 cells/µL and 1,170 ± 320 cells/µL, respectively; Welch's
approximate t-test; P = .03). To identify the level of
sFcRIII as an independent predictor of infection risk, 14 neutropenic patients with infections were each matched with two
neutropenic patients without infections, but with equal ANC. The
remaining patient (sFcRIII: 24 AU; ANC: 50 cells/µL) in the group
with infections could not be matched and was excluded.
Figure 1 shows the distribution of
sFcRIII levels in plasma of neutropenic patients with and without
bacterial infections, matched for ANC. The plasma levels of sFcRIII
were significantly lower in the neutropenic patients with infections, compared with the uninfected patients (54 ± 26 AU v 113 ± 62 AU, respectively; Welch's approximate t-test;
P = .0001). The mean difference between sFcRIII
levels in patients with and without infections was 59 AU (95%
confidence interval [CI]: 31 to 87 AU). Again, no
infections were reported for patients who had sFcRIII levels above
100 AU. All patients who suffered from an infection in the defined
period had plasma sFcRIII levels below 100 AU. The level of
sFcRIII was not statistically correlated to age or ANC. The two
groups had similar phenotype distributions of the FcRIIIb-NA and the
FcRIIa-131R/H polymorphisms.
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| Fig 1.
Plasma sFcRIII levels (AU) in neutropenic patients
with (n = 14) or without infections (n = 28) in the
period 3 months before to 3 months after a single sFcRIII
measurement. Each patient with an infection was matched with two
patients without infections who had approximately the same neutrophil
count. The mean sFcRIII levels (± standard deviation
[SD]) in patients with and without infections were 54 ± 26 AU and
113 ± 63 AU, respectively (Welch's approximate t test;
two-tailed P value = .0002). No statistically significant
differences were observed between the two groups regarding sex and age
distribution. FcRIIa-131R/H and FcRIIIb-NA(1,2) phenotype
distributions were similar in the two groups (3 × 2 contingency
table; P = .91 and P = .53, respectively).
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We compared the prognostic values of a plasma level of sFcRIII below
100 AU and an ANC below 1000 cells/µL regarding the infection risk in
the unmatched neutropenic patient group (n = 66). The ANC cut-off point
of 1,000 cells/µL was determined by ROC curves. This cut-off value
resulted in optimal specificity and sensitivity in our patient group
(not shown). As shown in Table 2, the
sensitivity and negative predictive value of the level of sFcRIII
are both 1.0, using a cut-off point of 100 AU. The sensitivity and
negative predictive value of the ANC, with a cut-off value of
1,000/µL, were 0.6 and 0.7, respectively.
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Table 2.
Prognostic Value of the Plasma Level of sFcRIII in
Patients With Neutropenia of Unknown Origin (n = 66) Regarding
the Risk of Infection
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Longitudinal data were obtained from 21 of the 66 patients (32%).
These patients were followed for a mean period of 9.4 months (range, 1 to 17) in which at least two sFcRIII levels were measured (mean,
2.95; range, 2 to 5). Laboratory findings were correlated to the
clinical situation of the patient at the time of blood sampling. To
investigate whether sFcRIII levels were constant in the healthy
population, five healthy individuals served as controls. Blood from
these donors was collected every 3 months for 1 year, and neutrophil
counts and plasma sFcRIII levels were measured. In these controls,
both parameters remained constant over time, and no bacterial
infections were reported in the study period (data not shown). The
neutropenic patients were divided into three groups: a group with
sFcRIII levels above 100 AU without infections, a group with
sFcRIII levels below 100 AU without infections, and a group with
sFcRIII below 100 AU with infections. As shown in
Fig 2, sFcRIII levels above 100 AU were
only observed in patients without infections. In 2 particular patients
(Table 3, data not plotted in Fig 2), an
increase in sFcRIII level to values above 100 AU was coincident with
a resolution of infection periods (not shown).
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| Fig 2.
Soluble FcRIII levels in neutropenic patients who were
followed longitudinally. Mean follow-up was 9.4 months (range, 1 to 17)
in which at least two blood samples were tested (mean, 2.95; range, 2 to 5). Patients without infections were divided in two groups: one with
sFcRIII levels above 100 AU ( ; n = 9) and one with sFcRIII
levels below 100 AU ( ; n = 6). All patients with reported
infections had sFcRIII below 100 AU ( ; n = 6).
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Table 3.
Soluble FcRIII Levels (AU), Neutrophil Counts
(mm 3), and Clinical Data of Two Neutropenic Patients
in Whom Resolution of Repeated Infection Periods Occurred
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| |
DISCUSSION |
Less than 5% of the total body amount of neutrophils circulate in the
peripheral blood. Nevertheless, extremely low numbers of circulating
neutrophils (<500/µL) correlate with the incidence of bacterial
infections.16 However, the infection risk in patients with
moderate to mild neutropenia (500 to 1,500/µL) is difficult to
estimate, and an additional parameter to evaluate the extent of
neutrophil defense is desirable. Previous work has shown that the
concentration of sFcRIII in plasma is a reflection of the total body
neutrophil mass and is correlated with the production of neutrophils in
the bone marrow.9,10 In the present study, we identified
the concentration of sFcRIII in plasma as a parameter that can be of
additional value in the prediction of the infection risk in patients
with chronic idiopathic neutropenia. We tested the hypothesis that a
normal sFcRIII level in plasma from neutropenic patients reflects a
normal total body amount of neutrophils and therefore indicates a
normal neutrophil defense and thus no increased infection risk.
Patients with an established decrease in neutrophil production (due to
malignancies in the bone marrow or drugs) or increased neutrophil
destruction (due to circulating neutrophil antibodies) were excluded.
The latter group of patients was excluded because part of the
autoantibodies in immune-mediated neutropenia has anti-FcRIII
specificity,17 which might interfere with sFcRIII measurement. Moreover, the fate of FcRIIIb derived from destroyed neutrophils is unknown, rendering interpretation of sFcRIII levels in plasma from patients with immune-mediated neutropenia difficult.
In 66 patients with neutropenia of unknown origin, no infections were
reported when plasma sFcRIII levels were above 100 AU. Overall, the
mean plasma sFcRIII level, as well as the mean neutrophil count,
were significantly lower in neutropenic patients with infections
compared with patients without infections. The lower plasma sFcRIII
level was probably not caused by the infection because recent work has
shown that bacterial infections do not affect neutrophil FcRIIIb
expression.18 In our group of patients, both neutropenia
and low levels of plasma sFcRIII reflected a compromised neutrophil
defense, predisposing to bacterial infections, but the plasma
sFcRIII level proved to be a more sensitive indicator. When we
eliminated the effect of the ANC on the infection incidence by matching
the patients with and without infections for the ANC, the differences
in sFcRIII levels between the two groups persisted. As in the
unmatched group, none of the neutropenic patients with a plasma
sFcRIII level above 100 AU suffered from an infection in the study
period. A similar conclusion can be drawn from the longitudinal data:
infections were not reported for patients whose sFcRIII levels were
above 100 AU during the follow-up period. Apparently, the number of
circulating neutrophils alone underestimates the neutrophil defense in
these patients. Because the range of sFcRIII levels in healthy
individuals with normal neutrophil counts is large (30 to 200 AU), with
60% having levels below 100 AU, the interpretation of sFcRIII
levels below 100 AU in neutropenic patients is complicated. Most of
these neutropenic patients may have a level of sFcRIII in the lower
part of the normal range together with an unusual distribution of
neutrophils, reflected by a low number of circulating neutrophils. Low
levels of sFcRIII can also be expected in the case of low neutrophil
FcRIIIb expression. The latter was found in healthy individuals with
heterozygous FcRIIIB gene deficiency, a trait that exists in
about 10% of the population.12,19 Neutrophils from these
individuals show half the membrane FcRIIIb expression and half the
amount of plasma sFcRIII of individuals with two FcRIIIB
genes. The lower level of sFcRIII in neutropenic patients with
infections seems not to be caused by a higher prevalence of
heterozygous FcRIIIB gene deficiency because there was no
increased prevalence of FcRIIIb-NA(1+2-) or -NA(1-2+) patients.
Furthermore, the finding that FcRIIIB gene deficiency is not
associated with an increased susceptibility to infections14
indicates that the gene deletion is probably equally distributed among
the infected and noninfected neutropenic groups. Quantitative Southern
blotting to determine the number of FcRIIIB genes could
definitively settle this question.
In childhood populations, correlations with susceptibility to
infections with several microorganisms have been described for both
neutrophil FcR polymorphisms.2-4 However, we found no
differences in FcRIIA-131R/H and FcRIIIB-NA(1,2)
gene distributions between the neutropenic patients with and
without bacterial infections, suggesting that, at least in adult
neutropenic patients, these polymorphisms do not play a major role in
the defense against bacteria.
We determined the test characteristics of sFcRIII measurement based
on our data. In our group of neutropenic patients, the sensitivity and
negative predictive value of an sFcRIII level above 100 AU regarding
the occurrence of a bacterial infection was 100%. Comparison of this
test with the prognostic value of an ANC below 1,000 cells/µL showed
that measurement of sFcRIII is of additional value in the estimation
of the infection risk in neutropenia. An ANC below 500/µL was a
specific indicator for infection, although sensitivity was weak
(specificity and sensitivity of 1.0 and 0.2, respectively). These data
suggest that measurement of plasma sFcRIII is especially useful in
moderate to mild neutropenia (500 to 1,500 cells/µL). The main
clinical implication of our data is that prophylactic antibiotics or
treatment with G-CSF might be safely omitted in neutropenic patients
with sFcRIII levels above 100 AU.
Correlations between several disease states and sFcRIII levels have
been described.20-22 However, most of these correlations can be attributed to a decreased bone marrow neutrophil production and
consequently low levels of plasma sFcRIII. In our patients, the
results of bone marrow examinations were similar in the groups with and
without infections. This might suggest that the plasma level sFcRIII
provides a more precise reflection of neutrophil production than does
microscopic examination of the bone marrow itself. We only included
patients with chronic idiopathic neutropenia in whom production and
lifetime of neutrophils were thought to be normal. Our data show that
in these patients an sFcRIII level above 100 AU can support the
clinician in his or her decision to adopt an expectative attitude.
Moreover, the hypothesis that plasma sFcRIII reflects bone marrow
neutrophil production and the results of the present study suggest a
possible applicability of sFcRIII measurement in more common
neutropenias, for example in assessing the severity of bone marrow
infiltration in leukemic patients. Prospective evaluation of different
patient groups may confirm this assumption.
| |
FOOTNOTES |
Submitted September 17, 1997;
accepted December 23, 1997.
Supported by Grant No. 900-512-092 from the Netherlands Organization
for Scientific Research (NWO).
Address reprint requests to Albert E.G.Kr. von dem Borne, MD, PhD,
Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Department of Experimental Immunohematology, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank the Department of Leukocyte and Thrombocyte Serology
of the CLB for collecting all of the patient samples and performing the
neutrophil NA(1,2)-phenotyping.
| |
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Abstract
Introduction
Abstract