Title: VALIDATION OF DIAGNOSES OF LIVER DISORDERS IN USERS OF SYSTEMIC
ANTIFUNGAL MEDICATION IN SWEDEN
Version: 1 Date: 18 Oct 2023
Reviewer's report:
This study looked at validation of registry data using ICD codes for the diagnosis of drug
induced liver injury due to systemic anti-fungal agents in Sweden. The study appeared to be
carefully done and well designed. It appears to have been part of a larger study looking at post-
marketing events for voriconazole. As such it did not include patients treated with amphotericin
or caspofungin.  The authors conclude that the positive predictive value for the diagnosis of
jaundice was high but the PPVs for toxic liver injury and hepatic failure were lower (approx
50% to 60%).
Comments.
It is an interesting study and well done. It appears to produce results similar to previous studies,
although the authors note these studies were not homogeneous in either populations or methods.
I think it would be helpful if the authors could indicate where they feel this kind of data from
registries could be useful. Is this kind of registry data useful for detecting a toxicity signal
which must then be interrogated by looking at the source data or is there some other use for
this approach?
Given that amphotericin and caspofungin were not included in the study perhaps the title could be
amended as a significant fraction of users of systemic antifungal medications were not included.
The definition of hepatic failure (line 142-4) used says "persistent disease 26 weeks from the
diagnosis of liver disease".  Is this a typo? - The definition of acute hepatic failure used in the
AASLD practice guidelines states: evidence of coagulation abnormality (INR > 1.5) and any
degree of mental alteration (encephalopathy) in a patient without pre-existing cirrhosis and with
an illness of < 26 weeks duration. This is the classical Trey and Davidson definition from 1970.
EASL guidelines also quote the Trey and Davidson definition and note that disease duration
of greater than 28 weeks before onset of encephalopathy is defined as chronic liver disease.
Subacute hepatic failure is disease to encephalopathy time of between 5 and 24 weeks.
I agree with the authors that jaundice can be due to causes other than liver failure. While the PPV
for jaundice was high it would be useful to know what proportion of the patients with definite
jaundice had evidence of severe liver injury or hepatic failure.
Title: VALIDATION OF DIAGNOSES OF LIVER DISORDERS IN USERS OF SYSTEMIC
ANTIFUNGAL MEDICATION IN SWEDEN
Version: 1 Date: 18 Oct 2023
Reviewer's report:
This study looked at validation of registry data using ICD codes for the diagnosis of drug
induced liver injury due to systemic anti-fungal agents in Sweden. The study appeared to be
carefully done and well designed. It appears to have been part of a larger study looking at post-
marketing events for voriconazole. As such it did not include patients treated with amphotericin
or caspofungin.  The authors conclude that the positive predictive value for the diagnosis of
jaundice was high but the PPVs for toxic liver injury and hepatic failure were lower (approx
50% to 60%).
Comments.
It is an interesting study and well done. It appears to produce results similar to previous studies,
although the authors note these studies were not homogeneous in either populations or methods.
I think it would be helpful if the authors could indicate where they feel this kind of data from
registries could be useful. Is this kind of registry data useful for detecting a toxicity signal
which must then be interrogated by looking at the source data or is there some other use for
this approach?
Given that amphotericin and caspofungin were not included in the study perhaps the title could be
amended as a significant fraction of users of systemic antifungal medications were not included.
The definition of hepatic failure (line 142-4) used says "persistent disease 26 weeks from the
diagnosis of liver disease".  Is this a typo? - The definition of acute hepatic failure used in the
AASLD practice guidelines states: evidence of coagulation abnormality (INR > 1.5) and any
degree of mental alteration (encephalopathy) in a patient without pre-existing cirrhosis and with
an illness of < 26 weeks duration. This is the classical Trey and Davidson definition from 1970.
EASL guidelines also quote the Trey and Davidson definition and note that disease duration
of greater than 28 weeks before onset of encephalopathy is defined as chronic liver disease.
Subacute hepatic failure is disease to encephalopathy time of between 5 and 24 weeks.
I agree with the authors that jaundice can be due to causes other than liver failure. While the PPV
for jaundice was high it would be useful to know what proportion of the patients with definite
jaundice had evidence of severe liver injury or hepatic failure.
Please review this paper.
user
Title: VALIDATION OF DIAGNOSES OF LIVER DISORDERS IN USERS OF SYSTEMIC
ANTIFUNGAL MEDICATION IN SWEDEN
Version: 1 Date: 18 Oct 2023
Reviewer's report:
This study looked at validation of registry data using ICD codes for the diagnosis of drug
induced liver injury due to systemic anti-fungal agents in Sweden. The study appeared to be
carefully done and well designed. It appears to have been part of a larger study looking at post-
marketing events for voriconazole. As such it did not include patients treated with amphotericin
or caspofungin.  The authors conclude that the positive predictive value for the diagnosis of
jaundice was high but the PPVs for toxic liver injury and hepatic failure were lower (approx
50% to 60%).
Comments.
It is an interesting study and well done. It appears to produce results similar to previous studies,
although the authors note these studies were not homogeneous in either populations or methods.
I think it would be helpful if the authors could indicate where they feel this kind of data from
registries could be useful. Is this kind of registry data useful for detecting a toxicity signal
which must then be interrogated by looking at the source data or is there some other use for
this approach?
Given that amphotericin and caspofungin were not included in the study perhaps the title could be
amended as a significant fraction of users of systemic antifungal medications were not included.
The definition of hepatic failure (line 142-4) used says "persistent disease 26 weeks from the
diagnosis of liver disease".  Is this a typo? - The definition of acute hepatic failure used in the
AASLD practice guidelines states: evidence of coagulation abnormality (INR > 1.5) and any
degree of mental alteration (encephalopathy) in a patient without pre-existing cirrhosis and with
an illness of < 26 weeks duration. This is the classical Trey and Davidson definition from 1970.
EASL guidelines also quote the Trey and Davidson definition and note that disease duration
of greater than 28 weeks before onset of encephalopathy is defined as chronic liver disease.
Subacute hepatic failure is disease to encephalopathy time of between 5 and 24 weeks.
I agree with the authors that jaundice can be due to causes other than liver failure. While the PPV
for jaundice was high it would be useful to know what proportion of the patients with definite
jaundice had evidence of severe liver injury or hepatic failure.
assistant