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Prognosis of cirrhotic patients with fungiascites and spontaneous
fungal peritonitis (SFP)
To the Editor:
We read the Letter to the Editor by Dr. Alexopoulou et al. on fun-
gal infections in patients with cirrhosis with great interest [1].
The authors concluded that anti-fungal agents may be added
empirically in cirrhotic patients who are unresponsive to stan-
dard antimicrobial therapy, since fungal infections often occur
in hospitalized cirrhotic patients with impaired renal function,
such as patients with refractory ascites. We analyzed a cohort
of cirrhotic patients with ascites [2–4] for fungal infections and
compared them to patients with bacteriascites or culture-positive
spontaneous bacterial peritonitis (SBP).
Among 126 patients with positive cultures from ascitic fluid
who were treated at our hospital in the years 2006–2011, we
registered 14 patients (11%) with at least one positive fungal
culture result, while 112 (89%) were found to have only bacteria
in their ascitic fluid. While the majority of those patients were
diagnosed as ‘simple’ bacteriascites or fungiascites (n = 74 and
n = 9, respectively), 38 and 5 patients also had elevated
polymorphic nuclear cell counts indicating SBP or spontaneous
fungal ascites (SFP), respectively. Aside from a higher preva-
lence of Child-Pugh stage C patients in the bacteriascites
group (p = 0.018), there were not statistically significant differ-
ences between patients with fungiascites/SFP and bacteri-
ascites/SBP (Table 1). The proportion of patients with cirrhosis
due to alcoholic liver disease (ALD) was 42.1% in the study by
Alexopoulou et al. and 58% in our study. Alcoholic etiology of
cirrhosis seems to be a predisposing factor for fungal infections
[5]. Indeed, we found all 5 cases of SFP in patients with ALD
etiology, whereas ALD etiology was found in only 53% of
patients with SBP.
Alexopoulou et al. detected exclusively Candida species (spp.,
mainly Candida albicans) with just one Candida parapsilosis case
showing resistance to caspofungin and all other Candida spp.
being sensitive to amphotericin B and fluconazole/voriconazole.
1452 Journal of Hepatology 2016 vol. 64 j 1446–1459
Po-Hong Liu1,2
⇑
Teh-Ia Huo1,3,
1
Department of Medicine, Taipei Veterans General Hospital,
Taipei, Taiwan
2
Faculty of Medicine, National Yang-Ming University School of
Medicine, Taipei, Taiwan
3
Institute of Pharmacology, National Yang-Ming University School of
Medicine, Taipei, Taiwan
⇑
Corresponding author. Address: Division of Gastroenterology
and Hepatology, Department of Medicine,
Taipei Veterans General Hospital,
No. 201, Sec. 2, Shipai Rd.,
Taipei 11217, Taiwan.
Tel.: +886 2 2871 2121x2050; fax: +886 2 2873 9318.
E-mail address: tihuo@vghtpe.gov.tw
In addition to Candida spp. (n = 10), we also isolated 3 cases of
Aspergillus spp. and 2 other fungi (Penicillium spp. and unspecified
yeast-like fungi). Bacterial co-colonization of ascitic fluid was
detected in 10 patients (53%) with fungiascites, and 3 (60%) with
SFP (mainly Enterococci and Staphylococci). Candida spp. was
isolated from 4 patients with SFP and Penicillium spp. was identi-
fied in the fifth. Microbes isolated from SBP were Gram-positive
bacteria in 47% and Gram-negative bacteria in 53%, with E. coli
being the most common germ overall (31%).
Among the 14 patients with positive ascitic fluid cultures for
fungi, only 6 patients received anti-fungal treatment. The
administered anti-mycotic was effective according to resistance
analysis in 2 cases of Candica albicans, while in 4 cases, micro-
bial resistance testing was not performed. All in all, 63% of
patients with bacteriascites or SBP and 57% of patients with
fungiascites or SFP received antibiotics (p = 0.697). However,
the fact that 79% of patients with fungus-positive ascites did
not receive any anti-mycotic treatment indicates that the
impact of fungal infections may be underestimated in clinical
routine, since the rate of sepsis was higher in patients with
fungiascites than in patients with bacteriascites (43% vs. 9%;
p = 0.040).
We previously showed that acute kidney injury (AKI) strongly
affects the outcome of patients with cirrhosis and ascites, and
SBP being one of the main triggers for AKI [6]. Here, we found
AKI developed not only after SBP (25/38, 66% of cases), but
also in 3/5 patients (60%) after SFP. The mean duration of
hospital stay (patients were censored at the time of death) was
comparable with 24 days (95% confidence interval (95% CI),
14–35 days) in SBP vs. 36 days (95% CI 8–64 days; p = 0.526) in
SFP, respectively.
The clinical course of our patients suffering from SFP was
very diverse. Patient 1 resolved the SFP episode, and had an
uncomplicated clinical course until the last follow-up visit
 JOURNAL OF HEPATOLOGY
Table 1. Patient characteristics.

Bacteriascites SBP Fungiascites SFP p value

Number of patients 74 38 9 5 Bacteriascites/SBP
vs. fungiascites/SFP
Paracentesis performed at
Outpatient clinic 12 (16%) 2 (5%) 1 (11%) 0 (0%) 0.051
Regular inpatient ward 45 (61%) 30 (79%) 4 (44%) 2 (40%)
ICU 17 (23%) 6 (16%) 4 (44%) 3 (60%)
Age [years] 57.0 ± 11.1 60.2 ± 9.9 58.4 ± 14.9 57.2 ± 5.8 0.218
Sex [m/f, (% male)] 61/13 (82) 26/12 (68) 6/3 (67) 4/1 (80) 0.600
Etiology
ALD 43 (58%) 20 (53%) 2 (22%) 5 (100%) 0.934
Viral 12 (16%) 5 (13%) 3 (33%) 0 (-)
Mixed ALD/viral 9 (12%) 3 (8%) 1 (11%) 0 (-)
Other 10 (13%) 10 (26%) 3 (33%) 0 (-)
Child class (B/C, %C) 29/45 (61%) 7/31 (82%) 7/2 (22%) 2/3 (60%) 0.018
MELD 17.8 (13.0-22.7) 26.0 (19.4-30.7) 18.3 (11.8-21.1) 19.3 (8.6-28.2) 0.270
Creatinine [mg/dl] 1.18 (0.88-1.54) 1.70 (0.80-2.74) 1.15 (0.94-2.09) 1.19 (1.17-1.97) 0.762
Bilirubin [mg/dl] 3.96 (1.80-7.27) 5.40 (2.68-11.63) 1.85 (1.06-17.31) 3.28 (0.84-9.53) 0.081
Albumin [g/L] 27.6 ± 6.2 25.8 ± 6.7 27.7 ± 3.9 22.7 ± 5.4 0.821
INR 1.38 (1.20-1.81) 1.84 (1.36-2.38) 1.24 (1.14-1.43) 1.66 (1.07-2.15) 0.292
Serum WBC [G/L] 6.2 (4.7-10.5) 9.0 (6.2-13.7) 9.3 (7.1-13.9) 13.4 (9.4-23.7) 0.169
Serum CRP [mg/dl] 2.42 (1.18-5.19) 6.21 (2.56-12.87) 6.05 (3.00-11.79) 16.93 (8.78-28.43) 0.018
Bacterial co-infection [n (%)] - - 4 (44%) 3 (60%) -
ACLF grades (hospitalized patients) 1: 9 (16%) 1: 2 (6%) 1: 1 (14%) 1: 1 (20%) 0.550
[n (%)] 2: 12 (22%) 2: 17 (50%) 2: 4 (57%) 2: 2 (40%)
3: 2 (4%) 3: 7 (21%) 3: 0 (0%) 3: 1 (20%)
Sepsis diagnosis during SFP/SBP 8/74 (11%) 8/38 (21%) 3/9 (33%) 3/5 (60%) 0.017
[n (%)]
Hospital stay [days (median, range)] 12 (0-57) 8 (0-67) 16.5 (2-33) 4 (1-50) 0.620
In-hospital mortality [n (%)] 12 (16%) 17 (45%) 3 (33%) 2 (40%) 0.524
Liver-related deaths [n (%)] 32 (43%) 19 (50%) 2 (22%) 2 (40%) 0.177
Cause of death Bacteriascites/SBP Fungiascites/SFP
Variceal bleeding 4 (14%) 0 0.151
Sepsis/sept. shock 10 (35%) 2 (40%)
Cardiovascular 1 (3%) 2 (40%)
ACLF 1 (3%) 0
Multi-organ failure 3 (10%) 1 (20%)
HCC/CCA 8 (28%) 0
Other GI bleedings 2 (7%) 0
Antibiotic treatment 70 (63%) 8 (57%) 0.697

All categorical data are shown as numbers (percentages). Numerical variables are shown as mean (± standard deviation) unless noted otherwise.

2 years later. Patient 2 did not resolve SFP and died 8 days after
the index paracentesis. Patient 3 died 2 days after his SFP
diagnosis. Patient 4 remained hospitalized for 50 days after
SFP diagnosis, but was discharged with improved health status
and lived for 7 more years. Patient 5 deceased the day after
SFP diagnosis. While Alexopoulou et al. found worse survival
rates in patients with fungal infections than in patients with
bacterial infections, in our study both bacteriascites and
fungiascites were associated with very poor survival and one
year mortality rates of 46% and 56%, respectively. This rate
was even higher in patients with SBP (82%) and SFP (60%).
The estimated median transplant-free survival was 16 days after
SBP and 8 days after SFP (p = 0.504). This underlines the
importance of identifying not only bacterial but also fungal
infections in patients with cirrhosis and ascites.
We cannot fully exclude an underreporting of fungal
infections in our patient cohort, since we did not systematically
perform fungal cultures in all patients. The low number of
patients with fungal infections might thus represent a statistical
limitation of our study. However, this letter is intended to
show the impact of fungal infections on the outcome of patients
with cirrhosis and ascites, rather than to systematically report
incidence rates of SFP. In this regard, we fully agree with
Dr. Alexopoulou et al. that fungal infections are of great clinical
importance in cirrhotic patients and want to emphasize the need
for performing fungal cultures of ascitic fluid to ensure optimal
clinical management.
Ultimately, the real clinical impact of systematic diagnosis
and treatment of fungal infections – particularly of ascitic fluid
– has to be assessed in well-designed prospective studies, since
our results are only based on retrospective analysis. Thus, the
potential benefits of performing fungal cultures systematically
all cirrhotic patients undergoing paracentesis remain to be
established in the future.

Journal of Hepatology 2016 vol. 64 j 1446–1459 1453

Letters to the Editor
Conflict of interest
The authors of this study declared that they do not have any con-
flict of interest or did not receive any funding with respect to this
manuscript.
References
[1] Alexopoulou A, Vasilieva L, Agiasotelli D, et al. Fungal infections in patients
with cirrhosis. J Hepatol 2015;63:1043–1045. http://dx.doi.org/10.1016/
j.jhep.2015.05.032.
[2] Schwabl P, Bucsics T, Soucek K, et al. Risk factors for development of
spontaneous bacterial peritonitis and subsequent mortality in cirrhotic
patients with ascites. Liver Int 2015. http://dx.doi.org/10.1111/liv.12795.
[3] Mandorfer M, Bota S, Schwabl P, et al. Nonselective b blockers increase risk for
hepatorenal syndrome and death in patients with cirrhosis and spontaneous
bacterial peritonitis. Gastroenterology 2014;146. http://dx.doi.org/10.1053/
j.gastro.2014.03.005 e1.
[4] Mandorfer M, Bota S, Schwabl P, et al. Proton pump inhibitor intake neither
predisposes to spontaneous bacterial peritonitis or other infections nor
increases mortality in patients with cirrhosis and ascites. PLoS One 2014;9.
http://dx.doi.org/10.1371/journal.pone.0110503 e110503.
[5] Lahmer T, Messer M, Mayr U, et al. Fungal ‘colonisation’ is associated with
increased mortality in medical intensive care unit patients with liver
Reply to ‘‘Prognosis of cirrhotic patients with fungiascites and
spontaneous fungal peritonitis”
To the Editor:
We appreciate the comments on our manuscript ‘‘Fungal infec-
tions in patients with cirrhosis” by Bucsics and colleagues, as well
as the opportunity to respond to them.
Bucsics and colleagues retrospectively recorded 14 cases with
positive fungal culture including 9 with fungiascites and 5
with spontaneous fungal peritonitis (SFP) among 126 patients
with positive cultures obtained from ascitic fluid. They isolated
Candida species from 10 of the cases, Aspergillus from 3, Penicil-
lium and yeast-like fungi from 2 cases with fungiascites, whereas
Candida species were isolated from 4 cases and Penicillium from 1
case with SFP. Candida species were exclusively isolated from 19
cases with spontaneous fungal peritonitis (SFP) in our study [1]. It
seems therefore that it is the most common fungus isolated in
ascitic fluid from cirrhotic patients. Recently, Bremmer and col-
leagues [2] and Hwang and colleagues [3] detected Candida spe-
cies in 100% and in 66% of the reported SFP cases, respectively.
Furthermore, Theocharidou and colleagues demonstrated that
Candida species were the causative pathogen in all 8 invasive fun-
gal infections isolated from blood or ascitic specimens in patients
with cirrhosis who were admitted to the intensive care unit [4].
Bucsics and colleagues reported concomitant bacterial infections
in ascitic fluid in 44% of fungiascites and 60% of SFP cases. These
results are consistent with both our findings [1] and with those of
previous investigators, showing that bacterial co-infection is
common in fungal cases [3]. Our criteria for the exclusion of sec-
ondary bacterial peritonitis were based on the Runyon and col-
leagues’ study [5]. However, our data were retrospectively
1454 Journal of Hepatology 2016 vol. 64 j 1446–1459
cirrhosis. Mycopathologia 2015;179:63–71. http://dx.doi.org/10.1007/
s11046-014-9825-6.
[6] Bucsics T, Mandorfer M, Schwabl P, et al. Impact of acute kidney injury on
prognosis of patients with liver cirrhosis and ascites: a retrospective cohort
study. J Gastroenterol Hepatol 2015. http://dx.doi.org/10.1111/jgh.13002.
Theresa Bucsics1
Philipp Schwabl1
Mattias Mandorfer1
⇑
Markus Peck-Radosavljevic1,2,
1
Division of Gastroenterology and Hepatology,
Department of Internal Medicine III,
Medical University of Vienna, Vienna, Austria
2
Dept. of Gastroenterology and Hepatology, Endocrinology and
Nephrology, Klinikum Klagenfurt am Wörthersee,
Klagenfurt, Austria
⇑
Corresponding author. Address: Div. of Gastroenterology and
Hepatology, Dept. of Internal Medicine III,
Medical University of Vienna,
Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Tel.: +43 1 40400 47440; fax: +43 1 40400 47350.
E-mail address: markus.peck@meduniwien.ac.at
collected and the misclassification of secondary bacterial peri-
tonitis cannot be excluded.
Bucsics and colleagues did not show higher mortality in
patients with fungal compared to those with bacterial infections.
However, it’s worth noting that the majority of their cases were
concerned with fungiascites and not SFP. An important point
stressing that SFP is a life-threatening condition is that sepsis
occurred in 60% of their SFP cases. Poor survival in SFP was also
described by both Bremmer and colleagues [2] and Hwang and
colleagues [3].
Nevertheless, the most concerning issue is that 79% of
patients reported by Bucsics and colleagues did not receive
any anti-fungal treatment. Similar results were reported by
Hwang and colleagues [3] showing that 66% of patients with
fungal infections were not treated with appropriate anti-fungal
agents. It is remarkable that 58% of patients with SFP were
not appropriately treated with any anti-fungal drug in our study
[1].
Bucsics and colleagues addressed the issue that fungal infec-
tions may be underestimated in clinical practice. Despite individ-
ual differences in various studies, SFP is a severe condition and
optimal management is needed. We fully agree with Bucsics
and colleagues that large prospective studies, where fungal cul-
tures are systematically obtained in patients with cirrhosis, are
needed in order to define the real prevalence and risk factors of
fungal infections in advanced cirrhosis and to consequently
assess the potential benefits of prompt diagnosis and targeted
treatment.