Reviewer's report 
 Invasive Pulmonary Aspergillosis in Patients with decompensated cirrhosis : case series Title: 
 2  6 November 2006 Version: Date: 
 koenraad H vandewoude Reviewer: 
Reviewer's report: 
General 
------------------------------------------------------------------------------- 
Major Compulsory Revisions (that the author must respond to before a decision on publication can be reached) 
The paper has gained quality with respect to content, linguistic quality; the case are presented in a better 
way. This paper may be accepted after a second revision. 
In the discussion section, some references to recent publications on invasive aspergillosis is critically ill 
patients should be inferred: Meersseman (ref 2), Garnacho Montero J Crit Care 2005; 9:R191-9 and 
Vandewoude K Crit Care 2006, 10: R31) - in order to point out that Aspergillus may be an emerging or 
underrecognized pathogen in non-hematological patients. A reference to the recognition of liver failure as 
predisposing factor to fungal infection, would also be valuable to set the scene in the discussion: Rolande 
N, Fungal infection ... Hepatology 1991; 12:1-9. 
In the discussion,it has been speculated that the treshold dose of steroid exposure may be lower in liver 
failure, or critical illness. I propose to insert a reference regarding this issue, eg Palmer LB Corticosteroid 
treatment as a risk factor for invasive aspergillosis in pat with lung disease. Thorax 1991; 46:15-20 - Lionakis MS Lancet 2003, 362: 1828. Hydrocortisone promotes the growth of Aspergillus in vitro hence it seems better to taper or stop such treatment in case of Aspergillus infection. 
Since all patients were critically ill, I suggest also to refer to the immunoparalysis due to critical illness 
(Hartemink KJ Immunoparalysis as a cause for invasive aspergillosis? Intensive Care Med 2003; 29:2068) 
In the conclusion section, I would suggest some rephrasing: 
' This case series generates the hypothesis that severe, decompensated liver cirrhosis may be considered as a host risk factor for the development of invasive aspergillosis. However, this assumption should be put 
into perspective, since in all cases, other risk factors for opportunistic infection are present, such as steroid 
exposure, antibiotic use and severe critical illness. In patients with advanced or decompensated liver cirrhosis and pneumonia, a primary or secondary fungal origin should be considered, if infiltrates progress in spite of adequate antibiotic therapy and respiratory 
insufficiency develops. Further diagnostic exploration is mandatory, including bronchoscopy and lavage, 
mycological sampling, and serology for Aspergillus antigen. Medical imaging may be contributive, but is less 
pathognomonic than in neutropenic patients. Early pre-emptive treatment with antifungals is warranted.' 
I propose to skip the sentence on combined antifungal treatment since this issue is not raised in this case 
series. 
Since in one of the cases the galactomannan is positive, it would be worthwile to set up an observational 
study on the diagnostic value of this test in liver cirrhosis patients with unresolving pneumonia. 
The suggestion of empiric treatment, seems not to be justified by the present data and other data in the 
current literature. Hence I insist to change the conclusion section. 
Finally, concerning the grim outcome in all cases, it should be stressed that the expected mortality bases on 
SAPS, is quite high for all these patients, and that the prognosis of sepsis and MOF in patients with 
advanced chronic liver failure is also dismal. 
------------------------------------------------------------------------------- 
Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the author 
can be trusted to correct) 
page 7 case 3 'hepatic encefalitis' should be 'encefalopathy' 
------------------------------------------------------------------------------- 
Discretionary Revisions (which the author can choose to ignore) 
 Unable to decide on acceptance or rejection until the authors have responded to the major What next?: 
compulsory revisions 
 An article of importance in its field Level of interest: 
 Acceptable Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
I declare I have no competing interests 
Prof. dr. Koenraad Vandewoude 
Intensive Care 
Ghent University Hospital De Pintelaan 185 9000 Gent 
Belgium 
Reviewer's report 
 Invasive Pulmonary Aspergillosis in Patients with decompensated cirrhosis : case series Title: 
 2  6 November 2006 Version: Date: 
 koenraad H vandewoude Reviewer: 
Reviewer's report: 
General 
------------------------------------------------------------------------------- 
Major Compulsory Revisions (that the author must respond to before a decision on publication can be reached) 
The paper has gained quality with respect to content, linguistic quality; the case are presented in a better 
way. This paper may be accepted after a second revision. 
In the discussion section, some references to recent publications on invasive aspergillosis is critically ill 
patients should be inferred: Meersseman (ref 2), Garnacho Montero J Crit Care 2005; 9:R191-9 and 
Vandewoude K Crit Care 2006, 10: R31) - in order to point out that Aspergillus may be an emerging or 
underrecognized pathogen in non-hematological patients. A reference to the recognition of liver failure as 
predisposing factor to fungal infection, would also be valuable to set the scene in the discussion: Rolande 
N, Fungal infection ... Hepatology 1991; 12:1-9. 
In the discussion,it has been speculated that the treshold dose of steroid exposure may be lower in liver 
failure, or critical illness. I propose to insert a reference regarding this issue, eg Palmer LB Corticosteroid 
treatment as a risk factor for invasive aspergillosis in pat with lung disease. Thorax 1991; 46:15-20 - Lionakis MS Lancet 2003, 362: 1828. Hydrocortisone promotes the growth of Aspergillus in vitro hence it seems better to taper or stop such treatment in case of Aspergillus infection. 
Since all patients were critically ill, I suggest also to refer to the immunoparalysis due to critical illness 
(Hartemink KJ Immunoparalysis as a cause for invasive aspergillosis? Intensive Care Med 2003; 29:2068) 
In the conclusion section, I would suggest some rephrasing: 
' This case series generates the hypothesis that severe, decompensated liver cirrhosis may be considered as a host risk factor for the development of invasive aspergillosis. However, this assumption should be put 
into perspective, since in all cases, other risk factors for opportunistic infection are present, such as steroid 
exposure, antibiotic use and severe critical illness. In patients with advanced or decompensated liver cirrhosis and pneumonia, a primary or secondary fungal origin should be considered, if infiltrates progress in spite of adequate antibiotic therapy and respiratory 
insufficiency develops. Further diagnostic exploration is mandatory, including bronchoscopy and lavage, 
mycological sampling, and serology for Aspergillus antigen. Medical imaging may be contributive, but is less 
pathognomonic than in neutropenic patients. Early pre-emptive treatment with antifungals is warranted.' 
I propose to skip the sentence on combined antifungal treatment since this issue is not raised in this case 
series. 
Since in one of the cases the galactomannan is positive, it would be worthwile to set up an observational 
study on the diagnostic value of this test in liver cirrhosis patients with unresolving pneumonia. 
The suggestion of empiric treatment, seems not to be justified by the present data and other data in the 
current literature. Hence I insist to change the conclusion section. 
Finally, concerning the grim outcome in all cases, it should be stressed that the expected mortality bases on 
SAPS, is quite high for all these patients, and that the prognosis of sepsis and MOF in patients with 
advanced chronic liver failure is also dismal. 
------------------------------------------------------------------------------- 
Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the author 
can be trusted to correct) 
page 7 case 3 'hepatic encefalitis' should be 'encefalopathy' 
------------------------------------------------------------------------------- 
Discretionary Revisions (which the author can choose to ignore) 
 Unable to decide on acceptance or rejection until the authors have responded to the major What next?: 
compulsory revisions 
 An article of importance in its field Level of interest: 
 Acceptable Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
I declare I have no competing interests 
Prof. dr. Koenraad Vandewoude 
Intensive Care 
Ghent University Hospital De Pintelaan 185 9000 Gent 
Belgium 
Please review this paper.
user
Reviewer's report 
 Invasive Pulmonary Aspergillosis in Patients with decompensated cirrhosis : case series Title: 
 2  6 November 2006 Version: Date: 
 koenraad H vandewoude Reviewer: 
Reviewer's report: 
General 
------------------------------------------------------------------------------- 
Major Compulsory Revisions (that the author must respond to before a decision on publication can be reached) 
The paper has gained quality with respect to content, linguistic quality; the case are presented in a better 
way. This paper may be accepted after a second revision. 
In the discussion section, some references to recent publications on invasive aspergillosis is critically ill 
patients should be inferred: Meersseman (ref 2), Garnacho Montero J Crit Care 2005; 9:R191-9 and 
Vandewoude K Crit Care 2006, 10: R31) - in order to point out that Aspergillus may be an emerging or 
underrecognized pathogen in non-hematological patients. A reference to the recognition of liver failure as 
predisposing factor to fungal infection, would also be valuable to set the scene in the discussion: Rolande 
N, Fungal infection ... Hepatology 1991; 12:1-9. 
In the discussion,it has been speculated that the treshold dose of steroid exposure may be lower in liver 
failure, or critical illness. I propose to insert a reference regarding this issue, eg Palmer LB Corticosteroid 
treatment as a risk factor for invasive aspergillosis in pat with lung disease. Thorax 1991; 46:15-20 - Lionakis MS Lancet 2003, 362: 1828. Hydrocortisone promotes the growth of Aspergillus in vitro hence it seems better to taper or stop such treatment in case of Aspergillus infection. 
Since all patients were critically ill, I suggest also to refer to the immunoparalysis due to critical illness 
(Hartemink KJ Immunoparalysis as a cause for invasive aspergillosis? Intensive Care Med 2003; 29:2068) 
In the conclusion section, I would suggest some rephrasing: 
' This case series generates the hypothesis that severe, decompensated liver cirrhosis may be considered as a host risk factor for the development of invasive aspergillosis. However, this assumption should be put 
into perspective, since in all cases, other risk factors for opportunistic infection are present, such as steroid 
exposure, antibiotic use and severe critical illness. In patients with advanced or decompensated liver cirrhosis and pneumonia, a primary or secondary fungal origin should be considered, if infiltrates progress in spite of adequate antibiotic therapy and respiratory 
insufficiency develops. Further diagnostic exploration is mandatory, including bronchoscopy and lavage, 
mycological sampling, and serology for Aspergillus antigen. Medical imaging may be contributive, but is less 
pathognomonic than in neutropenic patients. Early pre-emptive treatment with antifungals is warranted.' 
I propose to skip the sentence on combined antifungal treatment since this issue is not raised in this case 
series. 
Since in one of the cases the galactomannan is positive, it would be worthwile to set up an observational 
study on the diagnostic value of this test in liver cirrhosis patients with unresolving pneumonia. 
The suggestion of empiric treatment, seems not to be justified by the present data and other data in the 
current literature. Hence I insist to change the conclusion section. 
Finally, concerning the grim outcome in all cases, it should be stressed that the expected mortality bases on 
SAPS, is quite high for all these patients, and that the prognosis of sepsis and MOF in patients with 
advanced chronic liver failure is also dismal. 
------------------------------------------------------------------------------- 
Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the author 
can be trusted to correct) 
page 7 case 3 'hepatic encefalitis' should be 'encefalopathy' 
------------------------------------------------------------------------------- 
Discretionary Revisions (which the author can choose to ignore) 
 Unable to decide on acceptance or rejection until the authors have responded to the major What next?: 
compulsory revisions 
 An article of importance in its field Level of interest: 
 Acceptable Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
I declare I have no competing interests 
Prof. dr. Koenraad Vandewoude 
Intensive Care 
Ghent University Hospital De Pintelaan 185 9000 Gent 
Belgium 
assistant