contribution of (1,3)-beta-d-glucan (bg) to the
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CONTRIBUTION OF (1,3)-BETA-D-GLUCAN (BG) TO THE DIAGNOSIS OF 1
INVASIVE CANDIDIASIS AFTER LIVER TRANSPLANTATION 2
3
E Levesque1, S El Anbassi
2, E. Sitterle
2, F. Foulet
2, J.C. Merle
1, F. Botterel
2. 4
5
1 Department of Anaesthesia and Surgical Intensive Care - Liver ICU, AP-HP Henri Mondor 6
Hospital, Créteil, France – 2
Mycology, Microbiology Department, AP-HP Henri Mondor 7
Hospital DHU VIC, Créteil, France. 8
9
Running title: Beta-D-Glucan and liver transplantation 10
Key words: Liver Transplantation – invasive candidiasis – Serum (1,3)-beta-D glucan - 11
12
Text word count: 3297 words 13
Number of Tables: 3 14
Number of Figures: 2 15
16
Corresponding author: 17
Dr Eric Levesque 18
Department of Anaesthesia and Surgical Intensive Care - Liver ICU, AP-HP Henri Mondor 19
Hospital 20
51 avenue du Marechal de Lattre de Tassigny, 21
94100 Créteil 22
E-mail: [email protected] 23
24
JCM Accepts, published online ahead of print on 17 December 2014J. Clin. Microbiol. doi:10.1128/JCM.03018-14Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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Author contributions 25
Study concept and design: S El Anbassi, F Botterel 26
Data acquisition: S El Anbassi 27
Data analysis and interpretation: S El Anbassi, E Levesque, 28
Statistical analysis: E Levesque 29
Drafting of the manuscript: S El Anbassi, E Levesque, F Botterel 30
Critical revision of the manuscript: JC Merle, E Sitterle, F Foulet, F Botterel 31
Study supervision: JC Merle, F Botterel 32
33
This study was presented as a poster at the 23nd
ECCMID congress. The poster was entitled” 34
Contribution of (1,3)-beta-D-glucan (BG) to the diagnosis of candidiasis after liver 35
transplantation” and was presented by S. El Anbassi, E. Levesque, E. Sitterlé, F. Foulet, JC. 36
Merle and F. Botterel 37
38
Declaration of interests 39
The authors who took part in this study do not have any past or present relationship with the 40
manufacturers of any of the drugs involved/used for patients and did not receive any funding 41
from the manufacturer to carry out this research. 42
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Abstract 43
Introduction: Invasive candidiasis (IC) causes high morbidity and mortality after liver transplantation, 44
in part due to its delayed diagnosis. The fungal cell wall component (1,3)-beta-D-glucan (BG) could 45
be an early biomarker of IC. This preliminary prospective study was designed to evaluate the 46
contribution of BG to the diagnosis of IC after liver transplantation. 47
48
Methods: All consecutive patients who underwent a liver transplant at Henri Mondor Hospital in 49
France between January and June 2013 were enrolled prospectively in the study. They were monitored 50
weekly for colonisation by Candida and a colonization index (CI) was calculated. Serum samples 51
were tested for BG (Fungitell; Cape Cod Inc., USA) at least weekly between liver transplantation and 52
their discharge from hospital. 53
54
Results: A total of 52 patients were enrolled, with a median age of 55 [31-69] years (including 39 male 55
patients). The median MELD score was 27 [6-40]. Cultures from 42 patients (81%) yielded Candida 56
spp, the most common Candida species isolated being C glabrata (47%). Six cases of documented IC 57
were found in four out of the 52 patients. On the day the clinical diagnosis of IC was made, a score 58
based on combining two sequential BG-positive samples (> 146pg/ml) and a colonization index ≥0.5 59
revealed sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value 60
(NPV) values of 83%, 889%, 50% and 97.6%, respectively. 61
62
Conclusion: The detection of BG, associated with candida colonization, may be a promising tool 63
based on a high NPV that can rule out IC in high-risk patients. 64
65
Abstract word count: 248 words 66
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Introduction 67
Liver transplant recipients are at a relatively high risk of developing invasive fungal disease (IFD) (1-68
4). The most common invasive fungal pathogen is Candida spp., followed by Aspergillus species (1, 69
5-6). Such infections develop in 5% to 10% of transplant recipients and are a major cause of post-70
operative morbidity and mortality (4,7-9). This is in part related to a delayed or missed diagnosis 71
because of the lack of sensitivity and specificity of the diagnostic tests currently available (1, 10-11). 72
A serological diagnostic method, the quantification of the (1,3)-beta-D glucan (BG), was recently 73
recommended in the ESCMID guideline on the detection of candidemia in adults (12). BG is a cell 74
wall constituent found in many pathogenic fungi, including Candida, Aspergillus and Pneumocystis, 75
and it can be detected in patient serum during invasive disease caused by these fungi. In a meta-76
analysis, Karageorgopoulos et al. showed that BG detection displayed good sensitivity and specificity 77
for the diagnosis of IFD in the general population (13). In the setting of invasive candidiasis (IC), the 78
detection sensitivity of BG ranged from 64% to 100% (14-16). However, the BG assay has not been 79
assessed extensively in solid organ transplant populations. Only one study evaluated a pre-emptive 80
strategy that involved the use of BG monitoring to enable the early detection of IFD in liver transplant 81
recipients, and found its sensitivity and specificity for fungal infection to be 58% and 83%, 82
respectively (17). The same degree of sensitivity (64%) was observed in lung transplant patients using 83
a cut-off point set at 60pg/ml, but specificity was much lower (9%) (18). Today, the experts are in 84
agreement that the principal drawback of the BG assay is its lack of specificity in detecting 85
candidiasis. Indeed, several situations have been identified as having produced false positive results 86
regarding the detection of candidiasis: patients with Pseudomonas aeruginosa bacteraemia, patients 87
under treatment with fungus-derived antibiotics, intravenous immunoglobulins or albumin, and patient 88
exposure to gauze (15). 89
The paucity of data in the setting of liver transplantation was therefore the impetus behind this study. 90
Our objective was to assess the performance of serial measurements of serum BG levels for the 91
detection of IC in a liver transplant population. 92
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Patients and methods 93
We therefore carried out a preliminary, prospective study in liver transplant patients at Henri Mondor 94
Hospital. Between January and June 2013, all patients admitted consecutively to our Intensive Care 95
Unit (ICU) following liver transplantation were enrolled in the study. The demographic and clinical 96
characteristics, investigations and antimicrobial therapies were recorded prospectively. The patients 97
were studied during their hospitalization in and after the ICU. Our institutional review board approved 98
the study and the database was declared to the French Data Protection Authority (Commission 99
Nationale Informatique et Liberté) (no. 1699340). 100
101
Clinical and biological management 102
Following liver transplantation (LT), the recipients were hospitalized in our liver ICU. All patients 103
received similar postoperative intensive care with a standard triple immunosuppressive regimen that 104
included corticosteroids, mycophenolate mofetil and FK506 (tacrolimus) or cyclosporine, with 105
basiliximab (day 1 and day 4) in the event of a rising or initially high serum creatinine level. All 106
patients received postoperative antibiotic therapy for 48 hours (piperacillin) and trimethoprim-107
sulfamethoxazol (TMP/SMX) as prophylaxis against Pneumocystis jirovecii pneumonia. To prevent 108
cytomegalovirus (CMV) disease, pre-emptive therapy was instituted. Patients are monitored for 109
evidence of CMV replication, and antiviral therapy (valganciclovir or ganciclovir) was administered 110
pre-emptively to prevent progression to symptomatic clinical disease. Graft and recipient outcomes 111
were recorded prospectively for all transplanted patients. The clinical course of recipients was 112
followed for a minimum of 6 months after LT. 113
Identifying patients at an increased risk of fungal infection (re-transplantation, renal failure (creatinine 114
clearance <50 ml/min. or requiring replacement therapy), fulminant hepatic failure, primary-non 115
function, patients receiving thymoglobulin as an immunosuppressive agent, complicated or repeat 116
surgery, recipients with a MELD score prior to LT >30, more than 40 per-operative transfusions of 117
blood products, biliary-digestive anastomosis or yeast contamination of the organ preservation fluid) is 118
key to ensuring prevention (16). Patients affected by any of these factors received caspofungin at a 119
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dose of 70 mg on the first day and then 50 mg per day (or 70 mg per day if the recipient weighed 120
>80kg). The few patients who were only considered to be at risk of Candida infection but not 121
Aspergillus (patients with choledochojejunostomy or colonized at the time of liver transplantation by 122
Candida spp.) received fluconazole 400 mg per day for three weeks in the absence of Candida 123
glabrata, Candida krusei or the prior use of azoles. 124
In addition to clinical and laboratory evaluations to determine the presence of any infection, serum 125
was collected weekly during the patient's ICU stay and tested for BG using the Fungitell kit (Cape Cod 126
Inc., USA). These samples were stored at -20°C until batch testing was performed. The colonization 127
index (CI) of each patient was calculated on a weekly basis as the ratio between the number of distinct 128
non-blood body sites colonized by Candida spp. and the total number of body sites cultured (20-21). 129
For all patients, samples from the Candida surveillance sites (rectum, oropharynx, skin (axillary 130
surface) and urinary tract) were obtained on the day of admission and once a week thereafter until 131
discharge from the ICU or death. The patient was considered to be colonized when the threshold value 132
was ≥0.5 (20-21). 133
134
Definition 135
Invasive candidiasis (IC) included candidemia and deep-seated candidiasis, defined as the recovery of 136
Candida species from blood and/or a sterile site, respectively. Candida infections can manifest 137
themselves as peritonitis, candidemia, surgical anastomosis infection, urinary tract infection or wound 138
infection. IFD were thus classified according to the revised European Organization for Research and 139
Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria (22). Only patients with proven or 140
probable IFDs were evaluated as cases for the study. 141
Controls were defined as liver transplant recipients with no clinical or microbiological evidence of IC 142
(patients only colonized with Candida were also considered as controls). Serum samples had to be 143
collected from patients with proven or probable IFDs must have during the 7 days before and 21 days 144
after the diagnosis (or a 28-day diagnostic window). 145
146
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Statistical analysis 147
Continuous data are presented as medians and ranges. Fischer’s exact test (categorical variables) and 148
the Mann-Whitney test (continuous variables) were used to compare demographic data based on the 149
patient's IC status. The following parameters for diagnostic performance, and their 95% confidence 150
intervals, were calculated: sensitivity, specificity, Positive Predictive Value (PPV) and Negative 151
Predictive Value (NPV). Samples from patients without IFDs, from whom sample had been collected 152
for 7 days before and 21 days after determination of the presence of IFD were used to assess 153
performance. To identify the capacity to BG to diagnose invasive candidiasis, receiver operating 154
characteristic (ROC) curves was constructed. All statistical analyses were performed using SPSS 155
(version 18; SPPS, Inc, IBM, Chicago, IL). The areas under the curves (AUCs) provided the 156
discriminative ability of BG. The cut-off value for BD was identified using the highest Youden Index 157
(23). A p value lower than 0.05 was considered to be statistically significant. 158
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Results 159
Clinical characteristics 160
Between January 2013 and June 2013, 56 consecutive patients underwent LT, four of whom were 161
excluded from the analysis in this study, either because they died before any sample could be collected 162
(n=2) or no sample were collected during their stay in the ICU (n=2). Fifty-two patients were thus 163
enrolled in the present study. Their characteristics and risk factors for IC at the time of transplant are 164
shown in Table 1. The median age of the study population was 55 years [31-69], and 39 of the patients 165
(75%) were male. Twenty-seven liver recipients (52%) received antifungal prophylaxis with 166
fluconazole (n=6, 11%) or caspofungin (n=21, 40%). 167
168
Colonization index 169
After liver transplantation, and at their admission into the ICU, 12 patients (23%) presented with a 170
colonization index ≥0.5. Eight of these patients received caspofungin and two received fluconazole as 171
prophylaxis. The two remaining patients did not receive any antifungal therapy. During their ICU stay, 172
a total of 25 liver recipients (48%) had a colonization index ≥0.5, amongst whom 15 patients received 173
caspofungin, five received fluconazole and five received no prophylaxis. No effect of preventive 174
antifungal therapy on the quantification of yeasts and species counts was observed (data not shown). 175
In addition, the average number of positive sites colonized by patient remains equivalent during the 176
follow-up period and there is no significant difference between the number of colonized patients (with 177
CI≥0.5) over weeks, whether or not the patients were receiving antifungal prophylaxis and whatever 178
the prophylaxis. The most common Candida species isolated was C. glabrata (47%), followed by C. 179
albicans (42%) and C. parapsilosis. (4%). None invasive aspergillosis infection and Pneumocystis 180
pneumonia have been reported during this period in our patients. 181
182
IC and the diagnostic performance of BG 183
Based on the clinical criteria applied, 4/52 patients (8%) developed IC during their ICU stay. A total 184
of five IC infections were proven and one was probable. Among these patients, four with proven IC 185
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were affected by C. glabrata (n=3) or by C. glabrata and C. albicans (n=1), determined from 186
peritoneal fluid in a context of gastrointestinal perforation, and one patient had a positive blood culture 187
for C. parapsilosis. The patient with probable IC had a positive peritoneal fluid culture (C. albicans, 188
C. tropicalis and C. glabrata) with concurrent clinical signs and symptoms (Table 2). 189
For the BG test, 242 samples were obtained from the 52 patients. Thus, the average number of samples 190
obtained from each patient was 4.65 (range: 1 to 18). No correlation was observed between the CI and 191
the quantitative value of BG. 192
The mean BG value during the 28-day diagnostic window for patients with proven or probable IC was 193
significantly higher than the mean value in those without IC (285 ± 185 pg/ml vs. 136 ± 153 pg/ml, 194
respectively; p=0.02). 195
196
Determination of the BG cut-off for IC after liver transplantation. 197
Receiver Operating Characteristic curves were used to evaluate the potential for BD to diagnose IC 198
(Figure 1). Samples from patients without IFDs, from whom samples had been collected for 7 days 199
before and 21 days after determination of the presence of IFD were used to assess performance. The 200
area under the ROC curves was 0.72 (95% CI 0.63-0.81). Using the highest Youden Index, we 201
determined the most discriminative cut-off point from the ROC curve at 146 pg/ml for the diagnosis of 202
IC. 203
When applying a BG positive cut-off value of 146 pg/ml and using a single BG sample for the primary 204
analysis in proven and probable IC, the sensitivity, specificity, PPV and NPV of the BG assay were 205
respectively 100% (95% CI, 61 – 100), 61% (95% CI, 45 – 75), 25% (95% CI, 10 – 47) and 100% 206
(95% CI, 90 – 100). 207
The specificity and PPV of the test in cases of proven and probable IC increased from 61% and 25% 208
with one positive sample to 87% and 45%, respectively, when two sequential positive serum samples 209
were obtained (Table 3). Likewise, the specificity for proven and probable IC rose to 89% (95% CI, 76 210
– 96) when associating two sequential positive serum samples in patients with a colonization index 211
≥0.5 (Table 3). In patients with proven or probable IC, the median time elapsing between the first 212
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clinical sign of IC and the first BG value ≥146 pg/ml was 0 day (range: -21 to 14 days). Two 213
sequential positive BG samples preceded positive culture results in two of the six cases. The peak BG 214
value was reached a median of 10.5 days (range: -7 to 35 days) after the IC diagnosis. In all 6 patients, 215
following initiation of treatment, the BG decreased but with a kinetic variable among patients and 216
below the cut-off in three patients (Figure 2). 217
Two sequential BG positive serum samples with a CI >0.5 were observed in only five patients without 218
IC. The variables that might have influenced the assay results in these six patients were renal 219
replacement therapy (n=3), the administration of piperacillin-tazobactam (n=2), repeat surgery (n=3) 220
or a bacterial bloodstream infection (n=2). 221
In addition, from the 242 samples, 56 were obtained during the first week after transplant surgery and 222
186 after the first week. The mean BG level collected during the first week after transplant surgery 223
was 144±131pg/ml. During this week, based on an 146 pg/ml positive cut-off value, 30% (17/56) of 224
BG sample were positive in 16 patients without IC. In this period, only one patients (without IC) had 225
two sequential BG positive serum samples but with a CI < 0.5. 226
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Discussion 232
During this preliminary study, we investigated the usefulness of systematically monitoring of serum 233
BG levels following surgery in liver transplant recipients. Out of a total of 52 patients, four patients 234
(experiencing six episodes) developed proven or probable IC infections during their ICU stay. The 235
best diagnostic performance in this context was achieved by means of two consecutive positive BG 236
assay results (≥146 pg/ml) in patients with a colonization index ≥0.5. 237
Our findings indicate that in the setting of liver transplantation, serum BG measurements achieve good 238
diagnostic accuracy for the diagnosis of IC. Indeed, when comparing patients with proven or probable 239
IC and those without IC, the AUC-ROC was 0.72. 240
These findings are in agreement with those of Akamatsu et al., who conducted a study on the 241
usefulness of BG testing in liver transplantation (17). In their series of 180 living donor liver 242
transplants, the authors measured plasma BG levels prospectively using the Fungitec G test 243
(Seikagaku Biobusiness, Tokyo, Japan), which is not available in France. They found an AUC-ROC 244
curve for the detection of IFD using BG of 0.79, which was similar to our study. However, by 245
applying a calculated cut-off point for BG at 40 µg/ml, its sensitivity in detecting IFD during the 246
Japanese study was only 58%, lower that than observed during our study. This low sensitivity might 247
indicate a problem with false negatives, due to the heterogeneity of the 24 IFD cases diagnosed (14 248
cases of invasive candidiasis, 5 of aspergillosis, 3 of cryptococcal meningitis and 1 of Pneumocystis 249
pneumonia) over a period of a year. Although the infections detected by the BG assay include all 250
fungal infections, BG levels will usually be low or absent in patients with Cryptococcus infections 251
(24). In order to estimate the sensitivity of the BG assay during our study, we used the samples 252
obtained after the first week and only found six episodes of invasive candidiasis without any other IFI. 253
IC is the principal fungal infection observed during the weeks following liver transplantation. In this 254
context, Nguyen et al. evaluated the performance of the BD assay in the diagnosis of IC in a series that 255
included 35 solid organ transplant recipients (25). The sensitivity of the BG assay remained low 256
(56%), but this reflected poor detection by the BG assay of deep seated-candidiasis (25), something 257
we did not find in our series. 258
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Thus, the early positivity and excellent sensitivity of the BG assay that we observed during our study 259
suggest that the detection of BG in a population of liver transplant recipients, may support a decision 260
to initiate empirical antifungal therapy promptly. Indeed, Saliba et al. showed that patients with IFI 261
experienced significantly poorer graft survival and patient survival than those without fungal infection 262
(4), especially in the event of delayed treatment. However, the high proportion of false positives, and 263
the lack of specificity found with single BG-positive serum sample, highlights the need for an 264
immediate confirmation of any positive result by testing a second sample, in combination with a 265
standard diagnostic test (such as CI), and the identification of the context of false positive tests 266
(patients with concurrent bacteraemia, use of renal replacement therapy, patients receiving treatment 267
with fungus-derived antibiotics, intravenous immunoglobulins or albumin or exposure of the patient to 268
gauze (15)). In cases where the second sample is negative, and if no clinical symptoms are present, the 269
treatment should be withdrawn. At present, the colonization index remains a controversial method, but 270
before any more accurate predictors become available, or it can be used in combination with new 271
biomarkers, it remains is an important means of characterizing the dynamics of colonization (21). In 272
practice, the main recommendation that can be given from our results and our experience is to monitor 273
the BD every week when the result is negative (<146pg/ml) and to repeat samples (from 48h to 96 274
hours), when a first determination is positive, especially if the patient has a colonization index ≥0.5, in 275
parallel to the search of invasive fungal infection. 276
Another interesting finding was the frequency of positive BG results soon after liver transplantation 277
and the subsequent decline in values within the first week. This results from the introduction of BG 278
into the bloodstream via surgical gauze or transfusions, and reveals the weakness of the BG assay 279
during the early postoperative period (26). Thus, as recommended by others authors, the BG assays 280
seems useless to us during the first week (27). 281
We are aware of the limitations of this study. Aside from a limited sample size, our study was 282
restricted by the low frequency of cases of proven or probable IC. However, this was a preliminary 283
study in a liver transplant population, and we believe it is important to share our findings as they well 284
reflect the performance of BG in a population that sees a high level of false positives (15). There has 285
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been a dearth to date of studies evaluating the detection of BG in populations at a high risk of invasive 286
fungal infections. Further studies are now needed to confirm the interpretation criteria for BG (e.g. two 287
sequential BG samples ≥146pg/ml in patients with a colonization index >0.5), its performance in the 288
setting of liver transplantation and the optimum interval between collection of the two samples. In 289
addition, the efficiency of BG monitoring in the context of pre-emptive management strategies in liver 290
transplantation requires further investigation. The effect of antifungal therapy (prophylactic or 291
curative) on BG levels also necessitates additional study. 292
In conclusion, the present study confirmed that the detection of BG in serum seven days after liver 293
transplantation appears to be a promising tool to rule out IC in high-risk patients, based on its high 294
NPV. These findings suggest that early pre-emptive antifungal treatment should be considered in 295
patients with two sequential BG-positive serum samples associated with a colonization index ≥0.5, as 296
this may secondarily improve the patient’s outcome. 297
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Legends to Figures 412
Figure 1: Receiver operating characteristic (ROC) curves used to evaluate the power of BD in 413
the diagnosis of invasive candidiasis. AUROC (Area under ROC) values were 0.72 [95% confidence 414
interval (CI): 0.63 – 0.81]. 415
416
Figure 2: Change of the (1,3)-beta-D-Glucan levels after treatment. 417
418
Table 1: Characteristics and risk factors of invasive candidiasis at the time of transplant in the 419
52 study patients. Data are presented as medians [range] or n (%). Abbreviations: HBV: viral 420
hepatitis B; HCV: viral hepatitis C; D: Donor, R: Recipient; MELD: Model for End-Stage Liver 421
Disease; UNOS: United Network for Organ Sharing; LT: liver transplantation. 422
423
Table 2: Invasive candidiasis diagnosed during the surveillance period. Abbreviations: IC: 424
invasive candidiasis, LT: liver transplantation BG: the (1,3)-beta-D-Glucan assay, CI: colonization 425
index. 426
427
Table 3: Performance of the (1,3)-beta-D-Glucan assay (BG) and colonization index in detecting 428
invasive candidiasis in 52 liver transplant patients. BG: (1,3)-beta-D-Glucan assay; PPV: Positive 429
Predictive Value; NPV: Negative Predictive Value. CI : colonization index. BG-positive cut-off 430
value: 146pg/ml. 431
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Table 1: Characteristics and risk factors of invasive candidiasis at the time of transplant in the 52 study patients. Data are presented as medians [range]
or n (%). Abbreviations: HBV: hepatitis B virus; HCV: hepatitis C virus; D: Donor, R: Recipient; MELD: Model for End-Stage Liver Disease; UNOS: United
Network for Organ Sharing; LT: liver transplantation.
Variable Patients
n=52
Age (years) 55 (31-69)
Gender M/F 39/13
Indication for liver transplantation
Hepatocellular carcinoma
Cirrhosis
Other
Viral hepatitis (VHC and VHB)
Alcoholic liver disease
19 (37)
27 (52)
6 (11)
13 (25)
31 (59)
MELD score
MELD <20
MELD 20-30
MELD > 30
UNOS 1
27 (6-40)
19
8
25
25(48)
Cytomegalovirus status (R/D)
(+/-)/(+/+)/(-/-)/(-/+)
11/26/7/8
Invasive candidiasis risk factors
MELD > 30
Fulminant hepatic failure
Steroids before LT (> 20mg prednisolone equivalent)
Retransplantation
Graft type
Whole cadaveric liver transplant
Partial liver transplant (split)
Multi-organ transplantation (kidney/liver)
>40 UI Transfusion blood products
Renal Replacement therapy
Early reintervention after LT
Multifocal colonization by Candida spp
25 (48)
3 (6)
11 (21)
4 (8)
47 (90)
5 (10)
3 (6)
0
17 (33)
15 (29)
10 (19)
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Patient number
IC episodes number
Delay between LT and IC (days)
Localisation of IC Type of invasive candidiasis
Values BG (pg/ml) / IC
Prophylaxis treatment
Curative treatment
Outcome
1
1 46 peritonitis (C. glabrata) Proven 201 / 0.5 caspofungin voriconazole died 301 days after LT
2 252 candidemia (C. parapsilosis) Proven 356 / 0.8 caspofungin fluconazole
2 3 65 peritonitis (C. glabrata) Proven 500 / 0.8 caspofungin voriconazole died 81 days after LT
3 4 26 peritonitis (C. glabrata, C. albicans)
Proven 366 / 0.8 - caspofungin died 91 days after LT
4
5 12 peritonitis and candidemia (C. glabrata)
Proven 246 / 0.6 - caspofungin
died 280 days after LT
6 86 abscess and biliary prosthesis infection
(C. glabrata, C. albicans, C. tropicalis)
probable 500 / 0.5 - caspofungin
Table 2: Invasive candidiasis diagnosed during the surveillance period. Abbreviations: IC: invasive candidiasis, LT: liver transplantation, BG: the (1,3)-
beta-D-Glucan assay, CI: colonization index
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Sensitivity (%)
(95% CI)
Specificity (%)
(95% CI)
PPV (%)
(95% CI)
NPV (%)
(95% CI)
1 positive BG specimen 100 (61-100) 61 (45-75) 25(10-47) 100 (90- 100)
CI ≥ 0.5 100 (61-100) 58 (43-73) 24 (10-45) 100 (90-100)
2 sequential positive BG-specimen 83 (36-99) 87 (73-95) 45 (11-77) 97.6 (87-100)
2 sequential positive BG-specimen + CI ≥ 0.5 83 (36-99) 89 (76-96) 50 (18-81) 97.6 (87-100)
Table 3: Performance of the (1,3)-beta-D-Glucan assay (BG) and colonization index in invasive candidiasis diagnosis in 52 liver
transplant patients. BG: (1,3)-beta-D-Glucan assay; PPV: Positive Predictive Value; NPV: Negative Predictive Value. CI : colonization
index. BG-positive cut-off value: 146pg/ml.
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