ORIGINAL PAPER
ISSN 1425-9524
© Ann Transplant, 2014; 19: 667-673
DOI: 10.12659/AOT.892132
Fungal Infections in Liver Transplant Patients
Admitted to the Intensive Care Unit
Received: 2014.07.30
Accepted: 2014.09.18
Published: 2014.12.22
Authors’
Contribution:
Study Design A
Data Collection B
Analysis C
Statistical
Data Interpretation D
Manuscript
Preparation E
Literature Search F
Collection G
Funds
AE 1
D 2
F 2
C 3
C 4
B 5
Corresponding Author:
Source of support:
Background:
Material/Methods:
Results:
Conclusions:
MeSH Keywords:
Raghda Marzaban
Maged Salah
Ahmed M. Mukhtar
Reham A. Dwedar
Walaa Abdel-Latif
Ihab Mahmoud
1 Department of Endemic Medicine and Hepatogastroenterology, Faculty of
Medicine, Cairo University, Cairo, Egypt
2 Department of Anaesthesia and Intensive Care, Faculty of Medicine,
Cairo University, Cairo University, Cairo, Egypt
3 Department of Medical Microbiology and Immunology, Faculty of Medicine,
Cairo University, Cairo, Egypt
4 Department of Medical Microbiology and Immunology, Faculty of Medicine,
Ain Shams University, Cairo, Egypt
5 Department of Intensive Care, Wady El-Nile Hospital, Cairo, Egypt
Raghda Marzaban, e-mail: [email protected]
Departmental sources
Fungal infections have a significant impact on patient survival after liver transplantation, mostly caused by
Candida and Aspergillus. The clinical manifestations vary, and range from colonization, active local infection, to
severe invasive form. A high degree of suspicion is required for the early diagnosis and, accordingly, the optimal management of these infections. This study aimed to evaluate fungal infection in the Intensive care Unit
(ICU) in admitted liver transplant patients, focussing of etiologic agent, clinical/laboratory presentation (including mortality), and risk factors.
This retrospective study included living related liver transplanted patients admitted to the ICU. Clinical data
was collected, thorough clinical evaluation was done, and laboratory tests were performed. Microbiological examination detecting the presence of fungus in various samples, using cultures and serology, and imaging investigations were carried out in all patients.
This study included 23 cases of ICU-admitted liver transplant patients who were diagnosed with fungal infection. Candida was the most common fungal infection and occurred at a mean of 2 months after transplantation; while Aspergillus was less common and occurred later with worse laboratory findings. Invasive fungal infection constituted 43% of the diagnosed cases. Difference in mortality between Aspergillus and Candida was
insignificant, as was difference between patients with and without fungal infection.
Fungal infection among LT patients was common, including the invasive forms.
Aspergillosis • Candida • Liver Transplantation
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Background
Egypt was the first country to perform a living related liver transplant (LRLT) in the Middle East [1]. Knowledge about
common postoperative infections and opportunistic pathogens
is essential to improve the global care of the liver transplant
(LT) recipient [2]. Bacteria, and less commonly Candida infections, remain the predominant pathogens during the immediate post-operative period, especially during the first month
[3]. Fungal infections can be the major factor associated with
a poor prognosis in liver transplant recipients. Studies have
shown that 5–42% of liver transplant patients develop at least
1 fungal infection after transplantation [4]. There has been a
significant decrease in the incidence of invasive Candidiasis
and an insignificant increase in the rate of invasive Aspergillosis
[5]. The mortality associated with these infections is 25–69%;
however, Aspergillus-associated mortality has been found to
approach 100% if untreated [6]. Opportunistic invasive fungal
infection (IFI) plays a major role in immune-compromised patient outcome, but its diagnosis is still a question of debate.
Definite diagnosis is established by detection of fungi in tissue by biopsy or needle aspirate, although demonstration by
either culture or histological examination was sufficient to
distinguish molds from yeasts [7]. The incidence of IFI, which
is a life-threatening complication, is 7–42% in liver recipients,
with a mortality rate of 25–70% [8].
The aim of this study was to evaluate the epidemiology of
fungal infection among liver transplant patients in the intensive care unit (ICU).
Material and Methods
This was a retrospective study, and included 23 out of 140 patients (16.4%) who underwent living related liver transplantation (LRLT) and were admitted to the ICU at Wady El-Nile hospital, from 2011 to 2013. Inclusion criteria were adult (³18
years) patients with documented fungal infection. Exclusion
criteria were pediatric patients and those without documented fungal infection. Patients were grouped according to the
etiologic fungal agent.
All patients were subjected to thorough clinical and investigatory work-up. 1. Basic laboratory tests comprised complete
blood count (CBC), liver biochemical profile bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase
(ALT), albumin and international normalized ratio (INR), kidney function (urea and creatinine), and electrolytes (sodium
[Na+] and potassium [K+]). Hemoglobin (Hb) was considered
normal when Hb=13–17 g/dl, while anaemia was considered
mild at Hb ³10 g/dl, moderate at Hb 8–9.9 g/dl, and severe at
<8 g/dl. 2. Microbiology examination was carried out in various
body fluids: blood, bronchoalveolar lavage (BAL), urine, bile,
and wound to diagnose fungal and bacterial infection, whether
it co-existed with or predisposed to the reported fungal infection. More than 1 method should be used because fungi are
common in the environment and opportunistic fungi often occur in immunocompromised patients, making the interpretation of results with different laboratory methods difficult for
clinicians [9]. (i) Direct microscopic visualization in freshly obtained specimen after staining with Gram stain and potassium hydroxide. (ii) Culture is the criterion standard for the diagnosis of IFI, provided that the samples are from sterile sites
[9]. Blood samples were handled under complete aseptic condition – 0.5–1.5 ml were added to the blood culture bottle for
fungal culture and 3 ml were mixed with EDTA in a tube and
stored at –20°C until performance of polymerase chain reaction
(PCR). The blood culture bottles were incubated aerobically at
35°C and were subcultured every 48 h onto 2 Sabaroud’s dextrose agar plates and 1 blood agar (Oxoid, England) plate until
growth was detected or the bottle was discarded after 2 weeks.
One Sabaroud’s dextrose agar plate and the blood agar plate
were incubated at 35°C for detection of Candida and bacterial isolates. The other Sabaroud’s dextrose agar plate was left
at room temperature for up to 2 weeks for detection of filamentous fungal growth. All isolates were identified based on
colony morphology, microscopic examination of Gram-stained
film, and their biological activity [10, 11]. Fungemia was diagnosed by Bactec (Becton-Dickinson). (iii) Serology by Mannan
(Mn) antigen testing for Candida, and Galactomannan antigen
(GM) testing for Aspergillus as the detection of fungal cell wall
markers in serum, reported for galactomannan (GM), is relatively specific for Aspergillus species [12]. Both detect specific
cell-wall polysaccharide in ELISA format, such that detection
limit of Mn antigen is positive at ³0.5 ng/mL and equivocal at
0.25–0.5 ng/mL, while GM antigen is positive at optical density (OD) >0.5. For the diagnosis of co- existing bacterial infections, different specimens were incubated aerobically on blood
agar, chocolate agar and MacConkey agar and anaerobically
on blood agar for isolation of aerobic and anaerobic bacteria
for 24–72 hours at 37°C. The growing organisms were identified by conventional biochemical reactions. (iv) Molecular diagnosis using the polymerase chain reaction (PCR) assay may
be superior to the culture method for diagnosis of systemic
fungal infection in high-risk patients [13]. Total DNA was extracted using MagNA pure compact nucleic acid isolation kit
according to the manufacturer’s protocol. Universal sequence
fungal primers [14] is ITS1: (Cat. No. 03730964001, Roche,
Germany) according 5’-TCCGTAGGTGAACCTGCGG-3’ and ITS
4: 5’- TCCTCCGCTTATTGATATG-3’. The ITS region primers make
use of conserved regions of the 18S (ITS 1) and the 28 S (ITS
4) rRNA genes to amplify the intervening 5.8 S gene and the
ITS 1 and ITS 2 non-coding regions. For detection of Aspergillus
in positive samples for fungal infection, the sequence of the
primers used were 5’-TTG GTG GAG TGA TTT GTC TGC T-3’ and
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© Ann Transplant, 2014; 19: 667-673
ORIGINAL PAPER
5’-CTA AGG GCA TCA CAG ACC TG 3’, which target Aspergillusspecific sequences of the fungal 18 S rRNA gene. Amplification
was carried out in the LightCycler2.0 System (Roche, Germany)
using the Light Cycler DNA master SYBR green amplification
kit (Cat. No. 2015099, Roche, Germany).
3. Radiological examination by X-ray and high-resolution CT
are useful in the diagnosis of fungal infections. Pulmonary
fungal infections are characterized by central cavitation of
pulmonary lesions, infiltration, pulmonary nodules, and halo
or air-crescent signs [15]. 4. Statistical analysis was done using the Statistical Package for Scientific Studies (SPSS 21) for
Windows. Comparison between quantitative variables was carried out by t-test of 2 independent samples (if parametric) or
Mann-Whitney test (if non-parametric). Comparison between
qualitative variables was carried out by chi-square test (c2) or
Fisher’s exact test. Logistic regression model (multivariate analysis) was used to explore the significant risk factors of fungal
infections. Results are expressed in the form of P-value, such
that it is significant at <0.05
The primary outcome of this study was the prevalence of fungal infection among LT patients, and the secondary outcome
was their morbidity and mortality.
Results
This study included 23 post-LRLT patients who were admitted to the ICU and diagnosed with fungal infection. It was a
pilot study done in one of the few certified hospitals where
liver transplantation is carried out in Egypt. The 3-year prevalence of fungal infection was 23/ 140 (16.4%). Most fungal
infections (17/23 patients; 73.9%) were due to Candidiasis
(Group I) and Aspergillus (Group II) was less common (4/ 23
patients; 17.39%). Demographic features of the studied patients are shown in Table 1. Almost all of the studied patients
were transplanted for hepatitis C virus (HCV) hepatic complications (20/23 patients; 86.95%), mostly (18/ 20 patients; 90%)
due to HCV-induced cirrhosis. Three patients had Wilson’s disease. Two patients in Group II (33.3%) had mixed Aspergillus
and Candida fungal infection and no other fungal infection
was diagnosed. The mean time passed since LRLT, where fungal infection was diagnosed,was a few months, but Aspergillus
was reported later.
Laboratory results are shown in Table 2. None of them showed
a significant relation with fungal infection.
Predisposing factors to fungal infection in patients with fungal infection compared to those without is shown in Table 3.
None of the known predisposing factors showed a statistical difference.
Antifungal treatment was given in cases with fungemia, funguria when cell count ³5×104/ml, and in case of fungal detection in bile. In Aspergillus infection, voriconazole is given, while
in Candidiasis, we start with ketoconazole then shift to voriconazole in case of lack of response. Liposomal Amphotericin
B (LipoAmpB) is given in resistant cases. In this study, treatment was provided to half of the patients (13/23; 56.55%), but
3 cases remained uncured even after LipoAmpB.
Mortality was not significantly different between those
with fungal infection and those without (5/ 23; 21.7%, and
21/117; 17.9%, p=0.8), nor was it different between Candida
and Aspergillus infections (4/17; 23.5%, and 1/6; 16.7%, respectively, P=1). Not all reported mortality was attributed to
fungal infection – 2 patients died from severe fungal infection complicated by septic shock, 1 patient died from fungal and bacterial co-infection, and the others had underlying rejection.
Discussion
Worldwide, HCV is the first indication for liver transplantation
[16]. IFI is a rare but severe complication in LT patients [17].
In this study, fungal infection among ICU-admitted LT patients was diagnosed in 23 cases (16.4%), making the annual incidence 5.4%. The most common fungal infection was
Candidiasis (17/23 patients; 74%), followed by Aspergillus (6
patients; 26.1%) (2 were co-infected with Candida).
In this study, HCV was the commonest indication (86.95%) for
liver transplantation, mostly (90%) due to HCV-induced cirrhosis. This is in line with a report by Khalaf et al. that HCV cirrhosis, whether alone or mixed with schistosomiasis, was the
main indication for LDLT [18]. In another study, Khalaf et al.
reported that viral-related cirrhosis (43.1%) or mixed (48.3%)
were predominant [19]. The 2 reported cases with HCC were
induced by HCV – Egypt has high rates of HCV and is considered a large reservoir for chronic HCV [20].
The main finding of the present study was the 16.4% 3-year
prevalence of fungal infection, making a 5.4% annual incidence.
In line with our results, several authors have documented this
prevalence was 15.9–42% of LT recipients [21–24]. It was reported within a mean of 4 months after LT, with different timing according to etiologic agent. This was different from Shi
et al. who documented fungal infection occurring at 4–34 days
post-transplantation [21]. Fungemia was the commonest presentation (43.5%) followed by fungal chest infection (30.43%).
Bacterial co-infection was common (21.73%); all were gramnegative bacteria and not significantly related to the etiologic agent or the sample tested.
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Table 1. Demographic features of the studied patients.
Group II=
Aspergillus
(n=6)
Group I=
Candida
(n=17)
Total
(n=23)
P value
Male
18(78.3%)
14(82.4%)
4(66.7%)
Female
5(21.7%)
3(17.6%)
2(33.3%)
45.4±18.8
46.6±17.9
42.0±22.6
0.6
HCV-Cirrhosis
18(78.26%) 14(82.35%) 4(66.7%)
0.6
Metabolic
3(13%)
2(11.8%)
1(16.7%)
1.0
HCV-HCC
2(8.7%)
1(5.9%)
1(16.7%)
0.5
Pulmonary
4(17.4%)
2(11.8%)
2(33.3%)
0.3
CNS
1(4.3%)
1(5.9%)
0(0.0%)
1.0
CVS
1(4.3%)
1(5.9%)
0(0.0%)
1.0
Time passed since LRLT in months (mean ±SD)
4.0±7.9
2.0±3.1
9.5±13.9
0.07
CT chest
3(13%)
1(5.9%)
2(33.3%)
0.2
Blood
10(43.5%)
5(29.4%)
5(83.3%)
0.052
BAL
7(30.43%) 6(35.3%)
1(16.7%)
0.6
Urine
5(21.73%) 5(29.4%)
0(0.0%)
0.3
Bile
1(4.3%)
1(5.9%)
0(0.0%)
1.0
Culture
14(60.9%)
14(82.4%)
0(0.0%)
0.001
Serology
9(39.1%)
3(17.6%)
6(100.0%)
0.001
Molecular
14(60.9%)
14(82.4%)
0(0.0%)
0.001
5(21.73%) 3(17.6%)
2(33.3%)
0.6
E. Coli
3(60%)
2(66.7%)
1(50.0%)
Actinobacter
2(40%)
1(33.3%)
1(50.0%)
Sputum
2(40%)
1(33.3%)
1(50.0%)
1.0
Bile
2(40%)
1(33.3%)
1(50.0%)
1.0
Urine
1(20%)
1(33.3%)
0(0.0%)
1.0
Anti fungal treatment
13(56.5%)
7(41.2%)
0.02
Mortality
5(21.7%)
4(23.5%)
1(16.7%)
Gender
Age in years (mean ±SD)
Causes of transplantation
Causes of admission
Positive samples tested for fungal
infection
Diagnostic test
Bacterial co- infection
Type of bacterial co-infection
Site of bacterial co -infection
6(100.0%)
0.6
1.0
1.0
HCV – hepatitis C virus; HCC – hepatocellular carcinoma; CNS – central nervous system; CVS – cardiovascular system; LRLT – living
related liver transplantation; CT – computed tomography; BAL – bronchoalveolar lavage; E. coli – Echerechia coli.
All patients were anemic; most (20/23 patients; 86.95%) had
evident anemia (moderate and severe, equally present). This figure is higher than that reported in previous studies (4.3–28.2%)
[25,26], but anemia is a common finding among liver patients,
transplanted or not [27]. Elevated ALT was common among the
studied patients (16/23 patients; 69.56%), mostly less than
2-fold (10/16 patients; 62.5%).
Most fungal infections (21/23 patients; 91.3%) were attributed to a single agent (Candida or Aspergillus). Two patients had
mixed fungal infections.
Mortality was reported in 5/23 patients (21.7%). This is slightly lower than the 25–69% mortality reported by Eschenauer
et al. [4].
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Table 2. Laboratory results of the studied patients.
Mean ±SD
Laboratory result
Abnormal*
(g/dl)
Hb
CBC
WBC
Bilirubin
8.2±1.5
8.5±1.4
Albumin
INR
Urea
Kidney
functions
Creatinine
Electrolytes
(mg/dl)
7.5±1.5
0.2
3(13%)
3(17.6%) 0(0.0%)
0.5
10(43.5%) 8(47.1%) 2(33.3%)
0.7
Severe anaemia
10(43.5%) 6(35.3%) 4(66.7%)
0.3
(×103 cells/ml)
9.3±6.8
0.7
Leucocytosis
9(39.1%) 5(29.4%) 4(66.7%)
(×10 cells/ml)
153.8±133.0
Thrombocytopenia
15(65.2%) 12(70.6%) 3(50.0%)
0.6
(mg/dl)
5.6±8.7
0.4
Elevated
12(52.2%) 10(58.8%) 2(33.3%)
Normal
Liver
biochemical
profile
P value
Mild anaemia
AST
Trans
aminases
(IU/L)
Group II=
Aspergillus
(n=6)
Group I=
Candida
(n=17)
Moderate anaemia
3
Plt.
Total
(n=23)
81.1±96.6
9.0±7.0
155.9±142.3
7.0±9.8
10.2±6.9
0.2
147.8±113.8
0.9
1.8±1.6
88.5±110.4
0.4
60.0±37.2
0.5
12(52.2%) 10(58.8%) 2(33.3%)
0.4
£2 fold
7(30.4%) 4(23.5%) 3(50.0%)
0.3
>2 fold
4(17.4%) 3(17.6%) 1(16.7%)
1.0
ALT
119.6±133.9
0.9
120.9±140.2
115.7±126.0
Normal
7(30.4%) 5(29.4%) 2(33.3%)
1.0
<2 fold
10(43.5%) 8(47.1%) 2(33.3%)
0.7
³2 fold
6(26.1%) 4(23.5%) 2(33.3%)
0.6
(mg/dl)
2.9±0.5
0.2
Low
21(91.3%) 15(88.2%) 1–1.2
1.5±0.9
Prolonged
7(30.4%) 5(29.4%) 2(33.3%)
1.0
(mg/dl)
78.4±49.5
0.7
2.9±0.5
1.6±1.0
76.1±41.0
2.7±0.3
6(100.0%)
1.2±0.09
1.0
0.09
84.8±73.0
Elevated
19(82.6%) 15(88.2%) 4(66.7%)
0.3
(mg/dl)
0.9±0.6
1.3±0.9
0.3
Elevated
2(8.7%) 0
2(33.3%)
0.06
0.8±0.3
Na
135.3±7.7
134.8±5.8
136.7±12.0
0.6
K
4.3±1.0
4.5±1.0
4.1±1.0
0.4
CBC – complete blood count; Hb – haemoglobin; WBC – white blood cells; Plt. – platelets; AST – aspartate aminotransferase;
ALT – alanine aminotransferase. * Abnormal regarding normal values.
In the current study, Candida infection constituted 73.9% of the
cases, which is similar to the 62–83% reported by Briegel et al.
[24]; Candida is the most frequent species causing fungal infection [8]. However, the rate we found was intermediate compared
results by Yamanouchi et al., who found Candida species in all
their tested samples [23], while Papas et al. diagnosed them in
over half of all invasive fungal infections in liver recipients [28],
and Shi et al. diagnosed it in 62.2% of cases [21]. Candidal infection was diagnosed at a mean of 2 months post-LT, which
agreed with Papas et al. who reported that superficial and invasive candidiasis occurred early, often during the first 1–3 months
after liver transplantation [28]. Moreover, it was mainly detected in sputum (35.3%) followed by candidemia (29.4%). This incidence was higher than that reported by Moreno et al., whose
reported rates of 2–8%[29]. Considering the patients studied
(ICU-admitted patients), our results agree with the conclusion
that 1/3 to 1/2 of cases of candidemia occur in the ICU [30].
It was related, although insignificantly, with worse hepatic
condition regardless of necroinflammatory reaction (e.g., e
higher transaminases) or synthetic function (e.g., higher bilirubin and INR).
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Table 3. Predisposing factors to fungal infection in patients with fungal infection compared to those who did not.
Patients with
fungal infections
(n=23)
Predisposing factors and mortality
Patients without
fungal infections
(n=117)
Univariate
P value
Multivariate
P value
Dialysis
0
3(2.6%)
1.0
1.0
Re-transplantation
0
1(0.9%)
1.0
1.0
Surgical intervention
0
5(4.3%)
0.6
1.0
Positive aspergillus Ag
0
5(21.7%)
Blood transfusion
Mean ±SD (median)
12.5±6.8 (12)
9.8±8.1 (9)
Plasma transfusion
Mean ±SD (median)
12.8±8.4 (10)
12.5±9.2 (10)
In this study, Aspergillus was the second most common fungal infection, which was similar to other reports like Paya [31],
and the reported prevalence (6/23; 26.1%) was also similar to
that of Paya, who documented it in up to one-quarter of IFIs
[31]. However, it was lower than that reported be Shi et al.
(32.4%) [21] and higher than that of Fortún‘s et al., who diagnosed it in 1–9.2% of LT recipients [32]. Aspergillus was reported occurring later, diagnosed at a mean time of 9 months
after LT. This agrees with the fact that Aspergillus is a rather
a late post transplant fungal infection [33]. Also Singh et al reported Aspergillosis with higher incidence and less invasion
at mean time ≥90 days post LT on comparing 2 cohort studies, earlier versus late ones [34]. Our relative figures of etiologic agents also agreed with Pappasa et al. (except for the
detection of Cryptococcus), who proved IFI in 7 patients (4%),
where 3 had invasive candidiasis, 3 had invasive aspergillosis, and 1 had disseminated cryptococcosis [35]
Also, in this study, Aspergillus was mostly detected in blood (5/6;
83.3%). Only 1 patient had Aspergillus in sputum, confirmed
by CT chest. This was contrary to several previous studies that
stated pulmonary infection was the most common Aspergillus
clinical presentation (90%) [33], and that as the lungs are the
definite or probable primary site of invasive Aspergillosis in
most patients [36]. Diagnosis was significantly associated with
serology. Regarding the laboratory results, despite insignificant
difference, creatinine was higher, and 2/3 (4/6; 66.6%) of the
patients had severe anaemia and leucocytosis. This confirmed
that patients with Aspergillus spp. have the worst prognosis [8].
Most of the treated patients (10/13; 77%) were cured, confirming the effectiveness of the scheduled antifungal therapy. Shi recorded overall treatment effectiveness in 91.9% of patients [21].
The recorded mortality in this series ranged from 16.7% in
Aspergillus infection to 23.5% in Candida, which suggested the
<0.001
1.0
0.053
0.3
0.7
0.9
unlikely diagnosis of IFI, as the mortality range was 25–70%
[8], up to 100% in invasive pulmonary Aspergillosis [37].
In this study, none of the enrolled patients had a significant
risk factor predisposing to fungal infection. Despite insignificant difference, blood transfusion and positive Aspergillus antigenemia were higher among patients with fungal infection,
and, conversely, dialysis, re-transplantation, and surgical reintervention were higher among those without fungal infection; thus none of them received prophylactic antifungal therapy, as it is required in selected patients to improve the quality
of life and assure survival [17]. Moreover, it does not reduce
overall mortality or the need for empirical antifungal therapy
[38]. Those risk factors are good predictors of IFI and, accordingly, guide prophylaxis in liver transplant recipients. The administration of L-AmpB in high-risk patients is independently
associated with a reduction of IFI [39].
Conclusions
Fungal infection among LT patients was a common presentation,
caused mainly by Candida and to a lesser extent by Aspergillus,
with insignificant mortality difference, or IFI incidence.
Acknowledgment
We would like to express our gratitude to the medical and the
administrative sectors, particularly, the information technology (IT) unit, in supporting this work.
Statement
This was an unfunded work, and the authors declare that there
was no conflict of interest in this study.
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