Accepted Manuscript Letter to the Editor Fungal Infections in patients with cirrhosis Alexandra Alexopoulou, Larisa Vasilieva, Danai Agiasotelli, Spyros P. Dourakis PII: DOI: Reference:
S0168-8278(15)00396-7 http://dx.doi.org/10.1016/j.jhep.2015.05.032 JHEPAT 5709
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
24 April 2015 20 May 2015 21 May 2015
Please cite this article as: Alexopoulou, A., Vasilieva, L., Agiasotelli, D., Dourakis, S.P., Fungal Infections in patients with cirrhosis, Journal of Hepatology (2015), doi: http://dx.doi.org/10.1016/j.jhep.2015.05.032
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Fungal Infections in patients with cirrhosis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Alexandra Alexopoulou*, Larisa Vasilieva, Danai Agiasotelli, Spyros P Dourakis
2nd Department of Internal Medicine, Athens University Medical School, Athens, Greece
Word count 793 Number of figures 1 Number of Tables 1
*Corresponding author. Dr. Alexandra Alexopoulou, 2nd Department of Medicine, Medical School, University of Athens, Hippokration General Hospital, 114 Vas Sophias St, Athens, Greece, Phone +30 210 7774742, Fax +30 210 7706871 E-mail address: [email protected]
Abbreviations: SFP, spontaneous fungal peritonitis; SBP, spontaneous bacterial peritonitis Key words: fungal infections; spontaneous fungal peritonitis; fungemia
1
Author Contributions: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
All authors participated in acquisition, analysis, interpretation of the data and drafting the paper Spyros P Dourakis participated in conception and design and revising the article All authors approved the current version of the article
Conflict of interest and financial support The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
2
To the Editor: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Sir, We read with interest the position statement based on the EASL Special Conference 2013 by Jalan et al [1] about bacterial infections in cirrhosis. Authors reported that treatment failure rate was due to multi-drug resistant bacteria. We would like to add that fungal infections may be one of the causes of treatment failure in cirrhotic patients. Fungal infections have mainly been described in cirrhotic patients hospitalised in intensive care units [2] and in those with alcoholic hepatitis [3].
We studied fungal infections in 185 cirrhotic patients with culture-positive infection who were hospitalized during the period 2008-2014. Specifically, patients
with
human
immunodeficiency
virus
infection,
previous
transplantation or any other type of immunodeficiency, multi-microbial infections, in peritoneal dialysis or with secondary bacterial peritonitis were excluded. Diagnostic paracentesis and inoculation of ascitic fluid and blood samples into blood culture bottles for aerobic, anaerobic bacteria and Sabouraud’s dextrose broth for fungi were performed at bedside in all cirrhotic patients. One hundred sixty six (89.7%) patients had bacterial infection alone [105 (63.2%) culture-positive spontaneous bacterial peritonitis (SBP) (in a total of 282 SBP cases according to the criterion of ascitic fluid neutrophil count more than 250/mm3) and 61 (36.8%) spontaneous bacteremia without SBP], 8 (4.3%) combined bacterial and fungal and 11 (6%) fungal infection only. From the 19 patients with fungal infection, 11 (58%) had spontaneous
3
fungal peritonitis (SFP) with positive ascitic fluid culture and 8 (42%) fungemia 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
(positive blood culture) without SFP.
Fungal infections were due to Candida spp [albicans (11), parapsilosis (2), spp (2), lusitania (1), famata (1), tropicalis (1), glabrata (1)]. All Candida species were sensitive to amphotericin B, fluconazole and voriconazole while only one (Candida parapsilosis) was resistant to caspofungin. The 42.1% of patients with fungal infections had alcoholic cirrhosis but they were not actively drinking. Patients with fungal compared to those with bacterial infections had hardly more advanced liver disease and age and more severe renal impairment. Total protein, albumin, neutrophil and white cell count in ascitic fluid did not differ between patients with fungal and those with bacterial infections (Table).
The median time of hospitalization before the diagnosis of fungal infection was 4 days (1-8) and all patients were treated either with third generation cephalosporins or meropenem or were under prophylaxis for SBP. Nine (47.4%) of the fungal infections were nosocomial, 7 (36.8%) health-careassociated [4] and 3 (15.8%) both. Only 9 (47.4%) patients were treated promptly with appropriate anti-fungal agents. The remaining died undiagnosed due to the delay of laboratory results.
Estimated median survival of patients with fungal infections was 8 (95% CI 2.3-13.7) days. Mortality rate at 1 month and 6 months was 57.9% and 89.5%, in patients with fungal and 28.9% and 53% in those with bacterial infection,
4
respectively (log rank, P=0.001) (Fig). Patients with SFP had similar survival 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
to those with fungemia (log rank, P=0.099). Furthermore, no difference in survival was demonstrated between patients with combined bacterial and fungal and those with fungal infections alone (log rank, P= 0.164).
In conclusion, fungal infections are an emerging problem in cirrhosis and are usually fatal. Delayed diagnosis due to low index of suspicion is common [5 6]. They may occur with or without bacterial infections especially in patients with impaired renal function and recent or current hospitalization, under antibiotic therapy or prophylaxis. Ascitic fluid characteristics can’t distinguish SFP from SBP. Blood and ascitic fluid culture for fungi may be considered in cirrhotic patients with nosocomial infections and anti-fungal agents may be added empirically to patients who are not getting better with standard antibiotics.
5
Fig. Comparison of survival between 19 patients with fungal (8 combined 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
bacterial and fungal and 11 fungal infection only) and 166 with bacterial infection
6
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
REFERENCES [1] Jalan R, Fernandez J, Wiest R, Schnabl B, Moreau R, Angeli P, et al. Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013. J Hepatol 2014;60:1310-1324. [2] Lahmer T, Messer M, Mayr U, Saugel B, Noe S, Schultheiss C, et al. Fungal "colonisation" is Associated with Increased Mortality in Medical Intensive
Care
Unit
Patients
with Liver
Cirrhosis.
Mycopathologia
2015;179:63-71. [3] Lahmer T, Messer M, Schwerdtfeger C, Rasch S, Lee M, Saugel B, et al. Invasive mycosis in medical intensive care unit patients with severe alcoholic hepatitis. Mycopathologia 2014;177:193-197. [4] Friedman ND, Kaye KS, Stout JE, McGarry SA, Trivette SL, Briggs JP, et al. Health care--associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann Intern Med 2002;137:791-797. [5] Hassan EA, Abd El-Rehim AS, Hassany SM, Ahmed AO, Elsherbiny NM, Mohammed MH. Fungal infection in patients with end-stage liver disease: low frequency or low index of suspicion. Int J Infect Dis 2014;23:69-74. [6] Hwang SY, Yu SJ, Lee JH, Kim JS, Yoon JW, Kim YJ, et al. Spontaneous fungal peritonitis: a severe complication in patients with advanced liver cirrhosis. Eur J Clin Microbiol Infect Dis 2014;33:259-264.
7
Table. Comparison of main and laboratory characteristics between cirrhotic patients with fungal (8 combined bacterial and fungal and 11 fungal infection only) and those with bacterial infection Characteristic
Fungal
Bacterial
P Value
(N 19)
(N 166)
Age, years
74 (60-76)
62 (55-73)
0.059
Sex, males (Ν, %)
12 (63.2%)
115 (69.3%)
0.586
Health-care associated
19 (100%)
47 (28.3%)
0.007
24 (18-30)
20 (15-26)
0.061
C-reactive protein (mg/L)
70.7 (22-113)
58.8 (25-108)
0.921
Leucocyte count x103/μl
8.1 (4.0-10.7)
7.5 (4.9-11.3)
0.627
Neutrophil count x103/μl
5.3 (2.1-9.4)
5.8 (3.5-8.6)
0.480
Platelet × 103/μl
108 (48-142)
101 (66-139)
0.947
Total bilirubin (mg/dl)
3.1 (1.4-9.2)
3.9 (2-9.4)
0.532
INR
1.7 (1.4-2.5)
1.55 (1.4-2.1)
0.186
Albumin (g/dl)
2.8 (2.4-3.2)
2.8 (2.4-3.3)
0.904
Creatinine (mg/dl)
1.6 (1.2-2.9)
1.1 (0.8-1.8)
0.034
Spontaneous fungal
Spontaneous
peritonitis
bacterial peritonitis
(N 11)
(N 105)
Total protein (g/dl)
1.9 (1.1-2.5)
1.4 (1.0-2.0)
0.169
Albumin (g/dl)
0.8 (0.6-1.1)
0.6 (0.4-0.9)
0.097
401 (357-1827)
570 (280-2512)
0.699
and/or nosocomial (Ν, %) MELD
Ascitic fluid characteristic
Neutrophil count x103/μl
Data are median (interquartile range) or numbers of patients (%)
Figure
S0168-8278(15)00396-7 http://dx.doi.org/10.1016/j.jhep.2015.05.032 JHEPAT 5709
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
24 April 2015 20 May 2015 21 May 2015
Please cite this article as: Alexopoulou, A., Vasilieva, L., Agiasotelli, D., Dourakis, S.P., Fungal Infections in patients with cirrhosis, Journal of Hepatology (2015), doi: http://dx.doi.org/10.1016/j.jhep.2015.05.032
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Fungal Infections in patients with cirrhosis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Alexandra Alexopoulou*, Larisa Vasilieva, Danai Agiasotelli, Spyros P Dourakis
2nd Department of Internal Medicine, Athens University Medical School, Athens, Greece
Word count 793 Number of figures 1 Number of Tables 1
*Corresponding author. Dr. Alexandra Alexopoulou, 2nd Department of Medicine, Medical School, University of Athens, Hippokration General Hospital, 114 Vas Sophias St, Athens, Greece, Phone +30 210 7774742, Fax +30 210 7706871 E-mail address: [email protected]
Abbreviations: SFP, spontaneous fungal peritonitis; SBP, spontaneous bacterial peritonitis Key words: fungal infections; spontaneous fungal peritonitis; fungemia
1
Author Contributions: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
All authors participated in acquisition, analysis, interpretation of the data and drafting the paper Spyros P Dourakis participated in conception and design and revising the article All authors approved the current version of the article
Conflict of interest and financial support The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
2
To the Editor: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Sir, We read with interest the position statement based on the EASL Special Conference 2013 by Jalan et al [1] about bacterial infections in cirrhosis. Authors reported that treatment failure rate was due to multi-drug resistant bacteria. We would like to add that fungal infections may be one of the causes of treatment failure in cirrhotic patients. Fungal infections have mainly been described in cirrhotic patients hospitalised in intensive care units [2] and in those with alcoholic hepatitis [3].
We studied fungal infections in 185 cirrhotic patients with culture-positive infection who were hospitalized during the period 2008-2014. Specifically, patients
with
human
immunodeficiency
virus
infection,
previous
transplantation or any other type of immunodeficiency, multi-microbial infections, in peritoneal dialysis or with secondary bacterial peritonitis were excluded. Diagnostic paracentesis and inoculation of ascitic fluid and blood samples into blood culture bottles for aerobic, anaerobic bacteria and Sabouraud’s dextrose broth for fungi were performed at bedside in all cirrhotic patients. One hundred sixty six (89.7%) patients had bacterial infection alone [105 (63.2%) culture-positive spontaneous bacterial peritonitis (SBP) (in a total of 282 SBP cases according to the criterion of ascitic fluid neutrophil count more than 250/mm3) and 61 (36.8%) spontaneous bacteremia without SBP], 8 (4.3%) combined bacterial and fungal and 11 (6%) fungal infection only. From the 19 patients with fungal infection, 11 (58%) had spontaneous
3
fungal peritonitis (SFP) with positive ascitic fluid culture and 8 (42%) fungemia 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
(positive blood culture) without SFP.
Fungal infections were due to Candida spp [albicans (11), parapsilosis (2), spp (2), lusitania (1), famata (1), tropicalis (1), glabrata (1)]. All Candida species were sensitive to amphotericin B, fluconazole and voriconazole while only one (Candida parapsilosis) was resistant to caspofungin. The 42.1% of patients with fungal infections had alcoholic cirrhosis but they were not actively drinking. Patients with fungal compared to those with bacterial infections had hardly more advanced liver disease and age and more severe renal impairment. Total protein, albumin, neutrophil and white cell count in ascitic fluid did not differ between patients with fungal and those with bacterial infections (Table).
The median time of hospitalization before the diagnosis of fungal infection was 4 days (1-8) and all patients were treated either with third generation cephalosporins or meropenem or were under prophylaxis for SBP. Nine (47.4%) of the fungal infections were nosocomial, 7 (36.8%) health-careassociated [4] and 3 (15.8%) both. Only 9 (47.4%) patients were treated promptly with appropriate anti-fungal agents. The remaining died undiagnosed due to the delay of laboratory results.
Estimated median survival of patients with fungal infections was 8 (95% CI 2.3-13.7) days. Mortality rate at 1 month and 6 months was 57.9% and 89.5%, in patients with fungal and 28.9% and 53% in those with bacterial infection,
4
respectively (log rank, P=0.001) (Fig). Patients with SFP had similar survival 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
to those with fungemia (log rank, P=0.099). Furthermore, no difference in survival was demonstrated between patients with combined bacterial and fungal and those with fungal infections alone (log rank, P= 0.164).
In conclusion, fungal infections are an emerging problem in cirrhosis and are usually fatal. Delayed diagnosis due to low index of suspicion is common [5 6]. They may occur with or without bacterial infections especially in patients with impaired renal function and recent or current hospitalization, under antibiotic therapy or prophylaxis. Ascitic fluid characteristics can’t distinguish SFP from SBP. Blood and ascitic fluid culture for fungi may be considered in cirrhotic patients with nosocomial infections and anti-fungal agents may be added empirically to patients who are not getting better with standard antibiotics.
5
Fig. Comparison of survival between 19 patients with fungal (8 combined 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
bacterial and fungal and 11 fungal infection only) and 166 with bacterial infection
6
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
REFERENCES [1] Jalan R, Fernandez J, Wiest R, Schnabl B, Moreau R, Angeli P, et al. Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013. J Hepatol 2014;60:1310-1324. [2] Lahmer T, Messer M, Mayr U, Saugel B, Noe S, Schultheiss C, et al. Fungal "colonisation" is Associated with Increased Mortality in Medical Intensive
Care
Unit
Patients
with Liver
Cirrhosis.
Mycopathologia
2015;179:63-71. [3] Lahmer T, Messer M, Schwerdtfeger C, Rasch S, Lee M, Saugel B, et al. Invasive mycosis in medical intensive care unit patients with severe alcoholic hepatitis. Mycopathologia 2014;177:193-197. [4] Friedman ND, Kaye KS, Stout JE, McGarry SA, Trivette SL, Briggs JP, et al. Health care--associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann Intern Med 2002;137:791-797. [5] Hassan EA, Abd El-Rehim AS, Hassany SM, Ahmed AO, Elsherbiny NM, Mohammed MH. Fungal infection in patients with end-stage liver disease: low frequency or low index of suspicion. Int J Infect Dis 2014;23:69-74. [6] Hwang SY, Yu SJ, Lee JH, Kim JS, Yoon JW, Kim YJ, et al. Spontaneous fungal peritonitis: a severe complication in patients with advanced liver cirrhosis. Eur J Clin Microbiol Infect Dis 2014;33:259-264.
7
Table. Comparison of main and laboratory characteristics between cirrhotic patients with fungal (8 combined bacterial and fungal and 11 fungal infection only) and those with bacterial infection Characteristic
Fungal
Bacterial
P Value
(N 19)
(N 166)
Age, years
74 (60-76)
62 (55-73)
0.059
Sex, males (Ν, %)
12 (63.2%)
115 (69.3%)
0.586
Health-care associated
19 (100%)
47 (28.3%)
0.007
24 (18-30)
20 (15-26)
0.061
C-reactive protein (mg/L)
70.7 (22-113)
58.8 (25-108)
0.921
Leucocyte count x103/μl
8.1 (4.0-10.7)
7.5 (4.9-11.3)
0.627
Neutrophil count x103/μl
5.3 (2.1-9.4)
5.8 (3.5-8.6)
0.480
Platelet × 103/μl
108 (48-142)
101 (66-139)
0.947
Total bilirubin (mg/dl)
3.1 (1.4-9.2)
3.9 (2-9.4)
0.532
INR
1.7 (1.4-2.5)
1.55 (1.4-2.1)
0.186
Albumin (g/dl)
2.8 (2.4-3.2)
2.8 (2.4-3.3)
0.904
Creatinine (mg/dl)
1.6 (1.2-2.9)
1.1 (0.8-1.8)
0.034
Spontaneous fungal
Spontaneous
peritonitis
bacterial peritonitis
(N 11)
(N 105)
Total protein (g/dl)
1.9 (1.1-2.5)
1.4 (1.0-2.0)
0.169
Albumin (g/dl)
0.8 (0.6-1.1)
0.6 (0.4-0.9)
0.097
401 (357-1827)
570 (280-2512)
0.699
and/or nosocomial (Ν, %) MELD
Ascitic fluid characteristic
Neutrophil count x103/μl
Data are median (interquartile range) or numbers of patients (%)
Figure
