Chromosomal Integration of HHV-6 in a Preterm Neonate: A Rare Case of Hyperleukocytosis and Clinical Implications

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The study and its findings/conclusions are of significant importance to communicate and the manuscript is well constructed to convey this information.

I would only suggest adding a comment regarding the potential that any current non-specific neonate genome screening/sequencing would identify this situation and if there might be other similar insertions that could be of interest to attempt to identify that might lead to other mis-diagnoses

Author Response

Thank you for your positive feedback on the significance and construction of our manuscript.

We appreciate your suggestion to include comments on the potential for non-specific neonate genome screening/sequencing. We have added a sentence discussing neonate genome screening.

Reviewer 2 Report

Comments and Suggestions for Authors

Your manuscript is about a case report with hyperleukocytosis and HHV6.

A more detailed description of what HHV6 integration in human genome is needed and also pointing some recent studies regarding specific populations - eg Japanese (10.1002/jmv.25244)

In conclusion section is would be helpful if you add some long term complications of this disease and also to mention if screening is recommended in general pregnant population.

Author Response

Thank you for your thoughtful review of our manuscript. We appreciate your insightful comments and suggestions for improving the clarity and depth of our work. 

1. We acknowledge the need for a more detailed explanation of HHV6 integration into the human genome. Additionally, we will reference recent studies, such as the one you provided (doi: 10.1002/jmv.25244), to highlight insights into specific populations, such as the Japanese. We have updated accordingly. 
2. As per your suggestion, we have included a sentence about the long-term clinical ramifications associated with ciHHV6. 

We appreciate your valuable feedback, which will undoubtedly strengthen the manuscript and improve its utility for the medical community. Your insights have guided us in refining our work to ensure its accuracy, relevance, and clinical applicability. We look forward to incorporating these revisions and resubmitting the manuscript for your consideration.

Reviewer 3 Report

Comments and Suggestions for Authors

In this case report, the authors presented an exceptional case of a preterm male neonate who exhibited hyperleukocytosis and was subsequently diagnosed with chromosomally integrated Human Herpes Virus-6 (ciHHV-6). The authors concluded that this case underscored the importance of considering unusual etiologies of neonatal hyperleukocytosis and conducting appropriate diagnostic tests, including whole blood quantitative PCR, to differentiate ciHHV-6 from active HHV-6 infection.

 

Comments:

This is an interesting case report. The reviewer has some comments as follows:

1.      One of the concerns is that the patient's information seems not to be enough. It can be more detailed, such as: is there a fever in this neonate? how has the body weight changed?

2.      The descriptions of the methods for sample collection and HHV-6 Laboratory Test procedures can be added and described in detail, including the repeated numbers.

3.      The data presentation can be some revised:

(1) In Table 1, when are samples collected for these HHV-6 laboratory tests? It can be clarified.

(2) In Figure 1, the units for cell counts can be revised: “(x103/ul)” changes to “(x10³/μl)”.

4.      The quality of the data shown in Table 1 and Figure 1 can be improved.

5.      The manuscript formation can be checked such as: lines 34 and 42, “mm3” changes to“mm³”; line 138, “1 × 106 copies/mL” changes to “1 × 10⁶ copies/mL”.

6.      The reference list in this case report is appropriate.

7.      The conclusions of this case report are consistent with the evidence.

Author Response

Thank you for your detailed and constructive comments on our case report.

1. We agree that additional patient information would enhance the report. We have included details regarding the absence of fever and changes in body weight.

2. The manuscript now includes detailed descriptions of the sample collection methods for HHV-6 laboratory test procedures.

3. Regarding data presentation:

• We have included the timing of sample collection for the HHV-6 laboratory tests in Table 1.

• The units for cell counts in Figure 1 have been revised from “(x103/ul)” to “(x10³/μl)”.

4. We have updated Table 1 and Figure 1 to improve the data quality.

5. The manuscript has been updated as per suggestion, including the correction of mm3” changes to “mm³” on lines 34 and 42; “1 × 106 copies/mL” to “1 × 10⁶ copies/mL on line 138.

6. Thank you for noting that the reference list is appropriate.

7. We are glad that you find the conclusions consistent with the evidence provided.

Reviewer 4 Report

Comments and Suggestions for Authors

 

The manuscript “Chromosomal Integration of HHV-6 in a Preterm Neonate: A 2

Rare Case of Hyperleukocytosis and Clinical Implications” is a nice case report of hyperleukocytosis is a neonate with respiratory distress syndrome and anemia of prematurity, necessitating neonatal intensive care management. High human herpesvirus 6 (HHV-6) DNA levels in whole blood led to a diagnosis of chromosomally integrated HHV-6 (ciHHV-6). The manuscript nicely reviews most of the available literature on this subject, is well-written and deserves publication after minor editing. For example, the phrase: Neonates with hyperleukocytosis are at risk of severe complications, including respiratory distress, cardiac issues, hyperuricemia, acute renal failure, infarction, and hemorrhage is not appropriate. Please, change cardiac issues with myocardial ischemia and infarction. In addition, the term leukostasis is appropriate and should be used to describe the complications associated with a high white blood cell count, albeit usually in the context of a hematologic malignancy. This case highlights the importance of considering unusual etiologies of neonatal hyperleukocytosis and conducting suitable diagnostic tests, such as whole blood quantitative PCR, to differentiate ciHHV-6 from active HHV-6 infection.

Comments on the Quality of English Language

Minor editing required.

Author Response

Thank you for recognizing the quality of our case report and the comprehensive review of the available literature.

We will revise the phrase "cardiac issues" to "myocardial ischemia and infarction" to provide a more accurate description of the potential complications.

Furthermore, per your valuable suggestion, we have incorporated the term "leukostasis" to describe the complications associated with a high white blood cell count.

We appreciate your feedback highlighting the importance of considering unusual etiologies of neonatal hyperleukocytosis and the need for appropriate diagnostic tests. We have updated the manuscript accordingly.