Atypically Protracted Course of Liver Involvement in Kawasaki Disease. Case Report and Literature Review

Round 1

Reviewer 1 Report

The authors reported a case of liver damage associated with Kawasaki disease that lasted for more than 6 months. Using a variety of antibody tests, the authors ruled out the possibility of infection or autoimmune disease as the cause of the liver damage and concluded that the liver damage was due to Kawasaki disease.

Hepatotoxicity associated with Kawasaki disease is usually seen early in the course of the disease, and its significance as a prognostic marker for coronary artery disease has been discussed. This type of hepatotoxicity improves rapidly with the resolution of acute symptoms. In some cases, hepatotoxicity may occur after the acute symptoms have resolved. It is suspected that drugs such as aspirin are involved, but the cause is not well understood.

In the present case, the latter course was followed by prolonged liver damage. The authors do not mention the time of onset of the liver injury. A discussion of this atypical mode of onset would be of interest to readers.

Author Response

REVIEWER #1 (CHANGES IN REVISED MS ARE HIGLIGHTED IN YELLOW)

The authors reported a case of liver damage associated with Kawasaki disease that lasted for more than 6 months. Using a variety of antibody tests, the authors ruled out the possibility of infection or autoimmune disease as the cause of the liver damage and concluded that the liver damage was due to Kawasaki disease.

Hepatotoxicity associated with Kawasaki disease is usually seen early in the course of the disease, and its significance as a prognostic marker for coronary artery disease has been discussed.

1. This type of hepatotoxicity improves rapidly with the resolution of acute symptoms.

Reply.  We thank the Reviewer for pointing out this issue. We added his/her comment in the Introduction section (page 6)  “Elevations in serum aminotransferases and/or gammaglutamyl-transpeptidase (GGT) documented in about one third/one half of patients are mild to moderate [1-5] and are described to be transient as they improve rapidly with the resolution of acute symptoms [6]”.

2. In some cases, hepatotoxicity may occur after the acute symptoms have resolved. It is suspected that drugs such as aspirin are involved, but the cause is not well understood.
3. In the present case, the latter course was followed by prolonged liver damage. The authors do not mention the time of onset of the liver injury. A discussion of this atypical mode of onset would be of interest to readers.

              Reply. We thank the Reviewer for pointing out also this issue.

1. In the CASE REPORT (page 1- 2) now we better specify

• timing of hypertransaminasemia detection [“already at onset (day 3 ) of his 2 week-long acute febrile phase of a classical KD…….” ] (page 1),
• timing and doses of aspirin treatment (page 2)
• absence of Reye’s syndrome signs.

In the DISCUSSION SECTION (page 4) moreover we comment that:

 “In our case, although the transaminase peak was observed during aspirin treatment, a Reye’s syndrome like related mild hepatotoxicity in addition to the usual KD related transient hypertransaminasemia was unlikely due to the normality of mental status, liver echogenicity, glucose and NH3 blood levels.”

Author Response File: Author Response.docx

Reviewer 2 Report

Author Response

REVIEWER #2 (CHANGES IN REVISED MS ARE HIGLIGHTED IN LIGHT BLUE)

Elevated transaminases in KD patients is a well-known condition that usually resolves during the recovery period.

1. In the case of prolonged hypertransaminasemia, I think it is right to investigate the possible underlying causes. It may be possible to find several underlying causes, which, as the authors also state, could be the trigger event of the KD itself.

Therefore, a priori attributing the cause of liver dysfunction to KD could be a misleading message

Reply: We thank the Reviewer for pointing out this issue

According to his/her suggestion, we modulated

• the Abstract (see last line page1)
• the Conclusion Section (page 4) as well: Due to the likely uncommonness of the event here described, those infectious/immune causes which could have acutely triggered both conditions still need to be investigated in first instance. Should hypertransaminasemia persist, pending specific markers of KD related liver dysfunction, a stepwise approach with careful evaluation of the cost-benefit ratio in the use of additional diagnostic resources is anyway warranted to search for an underlying KD-unrelated persistent/chronic hepatopathy. [16].

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

　The authors claim to have reduced the dosage of aspirin from a high dose to a low dose over the course of 8 weeks. However, they do not state when the dose was changed. I am wondering the relationship between the time of aspirin dose reduction and the time of peak liver damage. I think Figure 1. needs to be improved in order to examine the relationship between aspirin and liver damage.

1) The horizontal axis scale in Figure 1. is not evenly spaced.It is necessary to make the time axis evenly spaced in order to grasp the entire flow.
2) The amount of aspirin is not shown in Figure 1. It is necessary to draw the time when the aspirin dose was changed to a lower dose.

　If the reduction in aspirin dose and the peak transaminase levels are almost identical and the worsening of liver damage can be explained by the side effects of high-dose aspirin, it is difficult to find scientific value in this paper.

Author Response

Review Report Form REV 2  (changes = red text highlighted yellow) 

The authors claim to have reduced the dosage of aspirin from a high dose to a low dose over the course of 8 weeks.

1. However, they do not state when the dose was changed. I am wondering the relationship between the time of aspirin dose reduction and the time of peak liver damage. I think Figure 1. needs to be improved in order to examine the relationship between aspirin and liver damage.

Reply 1. We thank the Reviewer for his/her mindful objections.

In the revised version of the MS at pages 1 and 2, now we make more clear that:

“At age 4 months he was hospitalized because of a 4day long fever resistant to paracetamol/ibuprofen. At entry, classical KD diagnosis was made (five clinical criteria in addition to fever) and he received high-dose acetylsalicylic acid (ASA) until 48h after persistent defervescence. (i.e. 80 mg/kg/day x 5 days) subsequently switched to low-dose (3 mg/kg/day) for a total duration of 8 weeks after the onset of disease. “

(according to ref 19, Italian Society of Pediatrics =  80 mg/kg/day subdivided into four doses until 48h after persistent defervescence.)

2) The horizontal axis scale in Figure 1. is not evenly spaced. It is necessary to make the time axis evenly spaced in order to grasp the entire flow.

Reply 2. OK. Done (see also the request of Reviewer #2,  asking days/weeks from diagnosis instead of dates)

3) The amount of aspirin is not shown in Figure 1. It is necessary to draw the time when the aspirin dose was changed to a lower dose.

Reply 3. OK Done  

4) If the reduction in aspirin dose and the peak transaminase levels are almost identical and the worsening of liver damage can be explained by the side effects of high-dose aspirin, it is difficult to find scientific value in this paper.

Reply 4. We thank the Reviewer for his/her mindful comment. As we amply discuss in the MS, we fully agree that ASA may be one of the possible agents involved in the frequent early and short term hypertransaminasemia of per protocol ASA treated KD children including our patient (according to the Literature = Table 1 = median duration 7 days, ranging from 2 days to 4mos/ 99days; peaking 1-3 days; tendency to exhibit recovery at the 4^th/6^th up to the 15^th/17^th day  )

Although the objective of our report is not really to focus only the possible ASA related DILI, but rather to warn that the length of KD related self-limiting HTS (in our patient it was 7 months) may occasionally be longer than previously reported, we added further considerations about the possible insidious role of ASA in similar cases.

1. We added details on ASA treatment in patient series included in our Table 1 (see new Table 1)
2. We added the following clarifying points:

• “Still an atypically prolonged idiosyncratic ASA hepatotoxicity remains an open question…..(page 4)
• “Because ASA doses recommended by the American Academy of Pediatrics and the American Heart Association to attain an anti-inflammatory effect during the acute phase of KD are fairly high reaching up to 80-100 mg/kg per day, high dose-ASA related DILI risk remains a possible insidious confounder. The question of whether the benefits of high dose ASA warrant its continued use in KD however is not likely to get an answer presently since all prospective studies that have demonstrated the effectiveness of IVIG in treating KD also employed moderate to high doses of aspirin [21].(pages 4 -5)

Precisely because of the above challenge we have suggested a stepwise approach with careful evaluation of the cost-benefit ratio in the use of additional diagnostic resources when deciding to search for a possibly underlying KD-unrelated persistent/chronic hepatopathy.

Reviewer 2 Report

in the graph and text I would not put the dates but the days/weeks fron diagnosys

At entry in our pediatric hepatology unit (June 16th)??: I think it would be better indicate the week of disease

Author Response

Review Report Form REV 2 (Changes in the MS = red text;  highlighted light blue)

1. in the graph and text, I would not put the dates but the days/weeks frnm diagnosis

Reply 1. DONE in the revised Figure 1

2. At entry in our pediatric hepatology unit (June 16th)??: I think it would be better indicate the week of disease

Reply 2. Thank you for your suggestion. We indicate now also the week/month of disease.    

“Because of persistent isolated hypertransaminasemia with normality of the remaining liver and muscular tests, at the 9th week of disease the patient was addressed to our pediatric hepatology unit. “(page 2)  

Round 3

Reviewer 1 Report

I appreciate the efforts for revision.