Journal of Clinical Microbiology, May 1999, p. 1510-1517, Vol. 37, No. 5
0095-1137/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
New Enzyme Immunoassays for Sensitive Detection of Circulating
Candida albicans Mannan and Antimannan Antibodies: Useful
Combined Test for Diagnosis of Systemic Candidiasis
Boualem
Sendid,1
Marc
Tabouret,2
Jean Louis
Poirot,3
Daniel
Mathieu,4
Jeanine
Fruit,1 and
Daniel
Poulain1,*
Equipe INSERM 99-15, Laboratoire de Mycologie
Fondamentale et Appliquée, CH&U, Faculté de
Médecine, Pôle Recherche, F-59045
Lille,1 Sanofi Diagnostics Pasteur,
59114 Steenvoorde,2 Laboratoire de
Parasitologie-Mycologie, Hôpital Saint Antoine, 75012 Paris,3 and Service de
Réanimation Médicale et de Médecine Hyperbare,
Hôpital Calmette, Lille,4 France
Received 29 October 1998/Returned for modification 2 December
1998/Accepted 25 January 1999
 |
ABSTRACT |
Two standardized enzyme immunoassays for the serological diagnosis
of candidiasis were developed. The first one detects antimannan antibodies, while the second one detects mannan with a sensitivity of
0.1 ng/ml. These tests were applied to 162 serum samples
retrospectively selected from 43 patients with mycologically and
clinically proven candidiasis caused by Candida albicans.
Forty-three serum samples were positive for mannan, and 63 had
significant antibody levels. Strikingly, only five serum samples were
simultaneously positive by both tests. When the results were analyzed
per patient, 36 (84%) presented at least one serum positive by one
test. For 30 of them, positivity by one test was always associated with
negative results by the other test for any of the tested sera. For six patients whose sera were positive for either an antigen or an antibody
response, a balance between positivity by each test was evidenced by
kinetic analysis of sera drawn during the time course of the infection.
Controls consisted of 98 serum samples from healthy individuals, 93 serum samples from patients hospitalized in intensive care units, and
39 serum samples from patients with deep mycoses. The sensitivities and
specificities were 40 and 98% and 53 and 94% for mannanemia or
antibody detection, respectively. These values reached 80 and 93%,
respectively, when the results of both tests were combined. These
observations, which clearly demonstrate a disparity between circulation
of a given mannan catabolite and antimannan antibody response, suggest
that use of both enzyme immunoassays may be useful for the routine
diagnosis of candidiasis.
| |
INTRODUCTION |
Yeasts of the genus
Candida have been recognized as important agents of
hospital-acquired infections. They have become the fourth most common
isolate recovered from blood cultures in the United States
(23). Similarly, the rates of candidemia have increased
substantially in Europe as well (69, 70). Candidal infections occur on both medical and surgical services, but
approximately half of them occur in surgical intensive care units.
Depending on the hospital ward, the mortality rate attributable to
candidemia ranges from 40 to 60% (46, 73). Difficulties in
establishing an early and specific diagnosis of candidal infection are
among the recognized reasons for such high mortality rates. The
difficulties for clinical diagnosis lie in the absence of specific
clinical signs (1, 4). Difficulties for biological diagnosis
lie in the opportunistic character of yeasts. Their presence in
normally colonized body sites of immunocompromised patients does not
prove infection, and they are rarely isolated from infected deep organs or tissues including blood (43, 52, 55). Efforts have been made to find either antibodies against Candida albicans
molecules or Candida-derived molecules whose presence in
patient sera could indicate deep-tissue invasion. Tests have been
developed to detect C. albicans proteins (35, 39,
71), metabolites (62), DNA (5, 15, 63), and
polysaccharides. In this regard, a sensitive biochemical test for the
detection of glucan, a major structural polysaccharide of the cell
wall, has been made commercially available, and promising data from a
large number of centers have been documented with a large number of
serum samples from patients (29, 39, 40, 42). Like glucans,
mannans are major components of the C. albicans cell wall,
making up to 7% of the cell dry weight (26a). By contrast
to glucans, mannans are noncovalently bound at the cell wall surface
and are highly immunogenic (17). They correspond to a large
and complex repertoire of mannopyranose units linked by either 
-1,6,
-1,3, -1,2, or 
-1,2 linkages (61). Among these
units, oligomannose sequences corresponding to epitopes specific for
human and animal antibodies, either polyclonal or monoclonal, have been
identified; antibody recognition depends on both the type of linkage
connecting the mannose units and the length of the mannose chain
(17, 19, 22, 32, 47, 61, 65). These epitopes may also be
shared by the glycosidic moiety of a large number of different
mannoproteins or glycolipids, reinforcing the quantitatively major
character of mannose residues in C. albicans cells (64,
65). The use of mannan antigenemia (mannanemia) detection for the
immunodiagnosis of systemic candidiasis was suggested by Weiner and
Coats-Stephen (72) about two decades ago. Attempts to
improve the immunological detection of mannan involved the use of
immune complex dissociation by heating sera before performance of the
test and the use of monoclonal antibodies that react with defined
epitopes (21, 22, 53). These efforts resulted in
standardization and a high level of specificity. These tests, however,
like the commercially available Pastorex Candida, still lack
sensitivity due to the rapid clearance of the antigen from patients'
sera and the test format (latex agglutination) (21, 37, 39,
50).
In contrast to mannanemia detection, tests based on antimannan antibody
detection have been used less and less in the clinical diagnostic
mycology laboratory because they have been described both as poorly
specific and as poorly sensitive. The reasons for the poor specificity
and sensitivity could be attributed to the elevated antibody titers in
heavily colonized but uninfected hospitalized patients (44)
and the possible lack of antibody response in infected
immunocompromised patients (24). Although antimannan antibody and mannan antigenemia were used singly, to our knowledge, simultaneous assays for both components in the same sera have never
been performed. Thus, in this study, sera from patients with documented
candidiasis were tested for the presence of mannanemia and antimannan
antibodies. To facilitate the combined detection of both mannan and its
antibodies, we (i) developed a double-sandwich enzyme immunoassay (EIA)
using the monoclonal antibody used in the Pastorex Candida,
with increased sensitivity, and (ii) developed an EIA for the
simultaneous detection of antibodies. A total of 162 serum samples from
43 hospitalized patients were retrospectively selected because of the
presentation of clinical and mycological evidence of deep-seated
candidiasis caused by C. albicans and were assessed by the
methods that we developed for the presence of mannanemia and antimannan
antibodies. Our data demonstrate that the developed EIA format
increases the detection limit of mannan with increased sensitivity
without adversely affecting the test specificity. A striking finding in
this study is the observation that serum samples with a high mannanemia
response had a low (undetectable) levels of antimannan antibodies and
vice versa. This finding was consistent among patients in general and for a given patient during the time course of the disease.
| |
MATERIALS AND METHODS |
Patients.
Between January and December 1995, 162 serum
samples were retrospectively collected in two different university
hospitals from 43 patients (16 females and 27 males [mean age, 56 ± 17 years]) with proven candidiasis. The average number of serum
samples per patient in this group was 3.7 ± 2 (Table
1). The following criteria were applied
as retrospective selection rules when the laboratory and clinical files
were examined: (i) positive culture of specimens from normally sterile
sites (blood, bile, pericardial fluid, liver biopsy, drain, and wound
specimens) for C. albicans; (ii) availability of serum
samples obtained within a range of 1 week before and 2 weeks after
positive cultures; (iii) the presence of risk factors (cancer and
chemotherapy, abdominal surgery, AIDS, major health problems requiring
hospitalization in intensive care units [ICUs], and use of
broad-spectrum antibiotics, indwelling intravascular catheters, and
hyperalimentation; and (iv) the presence of an infectious syndrome
(namely, fever) that did not respond to antibacterial therapy but that
did respond to antifungal therapy.
View this table:
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|
TABLE 1.
Underlying diseases, culture data, and results of antigen
and antibody testing for patients with candidiasis
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Control sera.
Three groups of control sera were included in
this study. (i) Group 1 comprised 93 serum specimens from 23 hospitalized patients (7 females and 16 males [mean age, 45 ± 12 years]) without evidence of invasive candidiasis. This group of
patients was enrolled in a prospective study conducted in an ICU of
Lille University Hospital for 6 months, the study was designed for the
assessment of risk factors for nosocomial candidiasis. These patients
were under clinical and mycological survey for periods ranging from 1 to 74 days (mean, 12 days). Samples of blood, oral swabs, urine, and
stools were collected biweekly. We selected 23 patients. For 19 patients Candida colonization was documented in at least one body site, but there was no proven, probable, or even suspected Candida tissue invasion. In four patients, candidal
colonization was not detected.
(ii) Group 2 consisted of 39 serum samples from patients with deep
mycoses not caused by Candida. Twenty-two serum samples were
retrospectively selected from 12 patients with invasive pulmonary aspergillosis (severe neutropenic patients with persistent fever, despite treatment with broad-spectrum antibacterial agents, and pulmonary infiltrates that developed on the chest roentgenogram). Invasive aspergillosis was also confirmed by the detection of Aspergillus galactomannan in sera. Three of 12 patients
included in this group were infected with human immunodeficiency virus (HIV). Thirteen patients (one serum sample from each patient) were
diagnosed with cryptococcal meningitis. Cryptococcal infection was
confirmed by isolation of Cryptococcus neoformans from
cerebrospinal fluid as well as detection of circulating antigen by the
Pastorex Crypto latex agglutination test (Sanofi Diagnostics Pasteur,
Marnes-la-Coquette, France). Among these patients, six were known to
have been infected with HIV for at least 3 months and two had undergone
kidney transplantation. Four serum samples were obtained from four
patients diagnosed with Pneumocystis carinii pneumonia.
These sera were retrospectively obtained from two patients who had
undergone bone marrow transplantation, one HIV-infected patient, and
one patient who had undergone kidney transplant surgery. All patients
were investigated for pulmonary disease, characterized by dyspnea,
cough, and fever and accompanied by abnormal chest radiographs. In each
case, the diagnosis of pneumonia was confirmed by the presence of
P. carinii cysts in bronchoalveolar lavages.
(iii) Group 3 consisted of 98 serum samples from 98 healthy bloodNumerous approaches for the serological diagnosis of candidiasis
have concentrated on the detection of C. albicans-derived molecules. These molecules were detected either on the basis of their
antigenicity or through biochemical-enzymatic procedures. More recent
progress has been made on the latter methods, and kits are commercially
available for the detection of arabinitol (62) and glucans
(29, 39, 40, 42), whereas PCR-based tests for
Candida DNA detection are routinely performed in some laboratories (5, 15, 63). Immunological detection of
C. albicans protein antigens of 47 and 48 kDa have
represented promising advances (35, 39, 71), but the use of
the commercially available assay (Directigen; Becton Dickinson) for the
detection of the 48-kDa vacuolar enolase has been limited by its cost.
In contrast, the Cand Tec latex agglutination test has been widely used
as the first commercially available antigen detection test (3, 19,
31, 67); the still unknown nature and function of the target
antigen have nonetheless impeded its further development. An
interesting feature of the serological detection of C. albicans-derived antigens in patient sera, in contrast to the
detection of nonimmunogenic molecules, is that the detected molecules
may elicit an antibody response in infected patients. Depending on the
pathophysiological importance of the antigen, joint consideration of
patient antigenemia and antibody response can provide insight into the
evolution of the infection. Such diagnostic strategies are commonly
used in virology for the serological survey of either HIV or hepatitis B virus infections. These methods involved the kinetics of the serum
antibody response to the p24, gp41, and gp120 of the hepatitis B
surface, core, and e antigens, respectively, for the detection of
antigenemia (14). Surprisingly, with the exception of the use of the approach for the detection of the 47-kDa antigen, which has
been shown both to circulate and to elicit protective antibodies (36), such an approach has never been applied to the
serological diagnosis of candidiasis. This is particularly true for the
mannan, the major immunogen of the C. albicans cell wall,
which for two decades has been shown to induce antibodies in humans and
to circulate in patients' sera (34). These diagnostic
approaches have considered mannan to be a single molecule, but they
failed to take into consideration its chemical and immunological
complexity. Within the mannan, a large number of chemically defined
sequences of mannose residues have been identified (61).
Depending on the type of linkage between the mannose residues and the
mannosyl chain length, mannan-derived oligomannosides have been shown
to be involved in such basic processes as inhibition of
lymphoproliferation (41), binding to epithelial cells and
macrophages (6, 7, 16, 33, 59), induction of cytokines and
arachidonic acid derivatives (2, 9), and induction of
protective or nonprotective antibodies in animal models
(19).
Polyclonal and then monoclonal antibodies have been used to detect
circulating mannan in patients' sera by either EIA (53), radioimmunoassay (72), latex agglutination (3, 18,
37), or coagglutination (30). Some of these epitopes
have been preliminarily characterized, as for monoclonal antibodies AF1
and 5B2, which have been shown to correspond to -1,2-linked
mannopyraosyl units of the mannan acid-labile domain (11,
50). In the present study, we have used monoclonal antibody
EBCA1, which is used to sensitize the latex particles involved in the
commercially available test Pastorex Candida. Recent studies
have shown that the monoclonal antibody EBCA1 minimal epitope was among
a mixture of mannopentaoses present in the mannan acid-stable domain:
an -1,2-linked isomer and an isomer in which the fifth mannose was
-1,6 linked to the reducing unit of manno--1,2-tetraose
(22). Therefore, monoclonal antibody EBCA1 epitopes fit with
the more general structure
Man1-(2Man1)n-2Man, (where n is
0), a type of mannopyranose chain that has been proposed to
correspond to antigenic factor 1 (27, 61), which is
ubiquitous in yeast species (66). The monoclonal antibody
EBCA1 epitope has also been shown to be expressed on the glycan moiety
of a large number of C. albicans mannoproteins which, if
released, can be detected in patient sera. Previous studies on antigen
detection with monoclonal antibody EBCA1 by the Pastorex latex
agglutination test have shown a good specificity but a poor sensitivity
(21, 39, 50). Therefore, we decided to increase the
sensitivity of the test by developing an EIA format instead of a latex
agglutination assay format. By using this method, the detection limit
has been improved up to 0.1 ng of mannan per ml. As expected, this
resulted in an increase in sensitivity which allowed us to detect
antigenemia in 40% of the patients, whereas with the Pastorex system
antigenemia could be detected in only 28% of the patients. This
increase in sensitivity was not detrimental to specificity since only 3 of the 150 control serum specimens were positive; none of them was from
healthy blood donors, 1 was drawn from a hospitalized colonized patient, and 2 were from patients infected with Aspergillus
fumigatus and C. neoformans, respectively. Although no
mycological evidence of candidiasis was found for these patients, the
possibility that they could be infected or coinfected with C. albicans could not be completely ruled out. When the sensitivity
of EIA is compared to that of Pastorex for each serum sample from
patients with candidiasis, in general, values lower than 1.5 ng/ml
failed to give a positive Pastorex test result. This resulted, however,
in a limited gain in overall sensitivity since 43 serum samples were
positive by EIA, whereas 35 were positive by Pastorex. Consideration of
these results for each serum sample is more disappointing than those for each patient, but this illustrates one of the major limitations of
mannanemia detection tests, which lies in the transient character of
antigen circulation (25, 52). As a consequence, sensitivity is a function of the number of serum samples available from each patient. In this study, sensitivity of mannanemia detection dropped from 40 to 11% if data for patients for whom only one serum sample was
available are considered. Several mechanisms have been proposed to
explain this observation, among which we can find the quick degradation
of mannose oligomers by serum mannosidases (10) or the
binding of the mannose oligomers to soluble serum proteins (mannose
binding protein C3) (20, 26, 60) or membranous receptors of
phagocytes (16, 33, 59). However, the present study
demonstrates that the detection of a given mannan catabolite in sera
from candidiasis patients is inversely correlated to the presence of
antimannan antibodies. Whether this phenomenon is restricted to the
epitope that was detected (22) (the epitope has structural
similarities to C. albicans mannan-derived O-linked oligomannosides that inhibit lymphocyte proliferation
[41]) or fits with the more general phenomenon of
antigen clearance by immune complexes remains to be established. These
results also led us, like others recently (68), to
reconsider the diagnostic value of antimannan antibody detection. We
have found a specificity of 94% and a sensitivity of 53% for the EIA
for antimannan antibody detection. It must be stressed that this
sensitivity was calculated by including data for patients for whom the
diagnosis was established by mannanemia detection. The combined tests
had a sensitivity and specificity of 80 and 93%, respectively. With
regard to the ability of both tests to diagnose C. albicans
infection early in the course of infection, conclusions can be drawn
only from data for the available sera due to the retrospective
character of this study. For 18 of the 43 patients included in the
study, at least one serum sample was available before mycological
evidence of infection was gained. When considering the results for
these sera, six patients presented with mannanemia (in the absence of significant antimannan antibody levels), nine patients presented with
significant antimannan antibody levels (in the absence of mannanemia),
and sera from the remaining three patients were negative by both tests.
Evidence of antigenemia and an antibody response was gained an average
of 6.2 and 7.3 days, respectively, before mycological isolation of
C. albicans. However, this study is limited to patients
infected with C. albicans only and patients infected with
non-C. albicans Candida species were not included.
Preliminary results obtained with sera from patients infected with
Candida glabrata, Candida tropicalis,
Candida parapsilosis, and Candida krusei which,
together with C. albicans, account for more than 95% of
hospital Candida infections, are encouraging. This
observation is not surprising since these different species of the
Candida genus share both the EBCA1 epitope distribution on
their mannan and mannoproteins (22) (for antigen detection
tests) and a high level of cross-antigenic mannan reactivity (for
antibody detection tests) (61). This study has shown that
the combined performances of antigen and antibody detection by these
tests were similar, irrespective of the immunosuppression status of the
patient and the service. Evaluation of the utility of both tests in
prospective studies enrolling large numbers of patients at risk for
candidiasis (73) is necessary.
We are grateful to Mahmoud A. Ghannoum and Donald Mackenzie for
helpful suggestions on the manuscript. We thank also Gabriel Reboux
(Besançon) for providing the sera from patients with cryptococcal meningitis and Laurence Richard and Nadine François for expert technical assistance.
This work was supported by a grant from the "Programme Hospitalier de
Recherche Clinique du Ministère des Affaires Sociales, de la
Santé et de la Ville."
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Abstract
Introduction
30°C.
For individual sera, 100 µl of serum diluted 1/8,000 was applied to
each well, and the plate was incubated for 1 h at 37°C. After
washing, 100 µl of horseradish peroxidase-conjugated anti-human
immunoglobulins was then added, and the plates were incubated for
1 h at 37°C. After intensive washing, the reaction was revealed
by 30 min of incubation in darkness with 200 µl of
tetramethylbenzidine solution. The absorbance at a 
of 450/620 nm
was measured. The results were reported in arbitrary units (AU) in
relation to the results on the standard curve (Fig.
1).
) and
antimannan antibody response (
) detected by EIA. Patients 39 (a) and
43 (b) had systemic candidiasis. The arrow marks the date of
mycological isolation of C. albicans from blood and a drain.
The curves are drawn by using the interpolate regression.