IgM- and IgA-Enriched Intravenous Immunoglobulin Combined with Cryopreserved Human Amniotic Membrane for Pediatric Toxic Epidermal Necrolysis: A Case Report

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Editor, Dear Authors,

This case report describes the successful use of a treatment protocol based on intravenous IgM+IgA, low dose systemic steroids, Human Amniotic Membrane and Fluorescent Light Energy after a previous failure of standard treatment protocol with infliximab and IVIg.

The case is described in detail, well referenced and supported by sound immunological explanations.

I just have a few minor comments that should be addressed in order to further improve this article's quality:

1) please indicate corticosteroid weight-based dosage (XX mg/Kg);

2) I suggest adding in the abstract that the patient was initially unsuccessfully treated with IFX + IVIg

3) While SCORTEN is the standard score used to assess SJS/TEN severity, a bit of caution should be used when using it to reliably predict mortality in modern clinical settings, as several recent studies have demonstrated that it usually tends to overestimate mortality. See e.g. Strużyna, J., Surowiecka, A., Korzeniowski, T. et al. Accuracy of SCORTEN in predicting mortality in toxic epidermal necrolysis. BMC Med Inform Decis Mak 22, 273 (2022). https://doi.org/10.1186/s12911-022-02013-2; and Scott D. Imahara, James H. Holmes, David M. Heimbach, Loren E. Engrav, Shari Honari, Matthew B. Klein, Nicole S. Gibran, SCORTEN Overestimates Mortality in the Setting of a Standardized Treatment Protocol, Journal of Burn Care & Research, Volume 27, Issue 3, May-June 2006, Pages 270–275, https://doi.org/10.1097/01.BCR.0000216532.71360.9B. You might want to address this in the limitations and to reduce the attention given to the predicted mortality for your case.

Author Response

Comment 1: Please indicate corticosteroid weight-based dosage (XX mg/kg).

Response 1: The methylprednisolone dosage has been revised throughout the manuscript to include the corresponding weight-based dose (0.74 mg/kg/day) in Abstract (page 1, line 30) and in Case Report (page 3, line 120).

 

Comment 2: I suggest adding in the abstract that the patient was initially unsuccessfully treated with IFX + IVIg.

Response 2: We agree that this information provides important clinical context. Accordingly, the Abstract has been revised to specify that the patient initially received high-dose intravenous immunoglobulin (2 g/kg) and infliximab (5 mg/kg) at the referring hospital without apparent arrest of disease progression prior to transfer to our Burn Unit (page 1, line 26-28).

 

Comment 3: While SCORTEN is the standard score used to assess SJS/TEN severity, a bit of caution should be used when using it to reliably predict mortality in modern clinical settings, as several recent studies have demonstrated that it usually tends to overestimate mortality. See e.g. Strużyna, J., Surowiecka, A., Korzeniowski, T. et al. Accuracy of SCORTEN in predicting mortality in toxic epidermal necrolysis. BMC Med Inform Decis Mak 22, 273 (2022). https://doi.org/10.1186/s12911-022-02013-2; and Scott D. Imahara, James H. Holmes, David M. Heimbach, Loren E. Engrav, Shari Honari, Matthew B. Klein, Nicole S. Gibran, SCORTEN Overestimates Mortality in the Setting of a Standardized Treatment Protocol, Journal of Burn Care & Research, Volume 27, Issue 3, May-June 2006, Pages 270–275, https://doi.org/10.1097/01.BCR.0000216532.71360.9B. You might want to address this in the limitations and to reduce the attention given to the predicted mortality for your case.

Response 3: We appreciate this important observation and thank the Reviewer for highlighting these references. We expanded the limitations section in Discussion to note that the prognostic significance of the SCORTEN value reported in this case should be interpreted with caution, given evidence that the score may overpredict mortality in modern multidisciplinary treatment settings and has not been extensively validated in children (page 7, line 239-243).

 

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have done a fairly good job in writing this case report entitled "IgM- and IgA-enriched IV immunoglobulin combined with cryopreserved Human Amniotic Membrane for Pediatric Toxic Epidermal Necrolysis".  The author reports an 11-year-old girl who developed TEN involving 90% of the total body surface area after exposure to a NSAID with concomitant viral positivity.  The patient was transferred to Burn Unit on the sixth day.  Histopathology confirmed epidermal loss.  The patient was treated IgM- and IgA-enriched IV immunoglobulin over 72 hours and methylprednisolone 20 mgs daily for 30 days.  Cyopreserved amniotic membrane to trunk and limbs and FLE to the face.  Complete re-epithelialization occurred within 14 days without complications.  At six months, skin and mucosae were intact with only transcient dyschromia.  The authors conclude that this 11-yr old girl with TEN involving 90% TBSA,, treatment with IgM/IgA -enriched immunoglobulin, low dose corticosteroid and early staged cryopreserved amnion were associated with infection-free, complete re-epithelization and full functional recovery.  The authors mention some limitations of the study.  However, please note the following points:

1. The diagnosis of TEN was made on histopathology, so the histopathology findings on the biopsy may be presented.  
2. Were the eyes involved? if yes, describe the ophthalmologic findings.  If eyes were not involved please mention that they were not involved. please mention that they were not involved.
3. What type of viral infection, the patient was having.  Were any viral cultures done to determine the type of vral infection.  
4. Please explain why the authors did not perform the "mechanistic studies on skin or serum samples" in this child and how the pathophysiology interpretation relies on published data.  Explain what is meant by mechanistic studies on skin or serum samples.  

Comments on the Quality of English Language

The quality of English language used is acceptable.

Author Response

Comment 1: The diagnosis of TEN was made on histopathology, so the histopathology findings on the biopsy may be presented.

Response 1: We thank the Reviewer for this valuable suggestion. We have expanded the histopathological description in the Case Report section (page 3, line 103-108). The revised manuscript now reports the presence of complete epidermal loss with full-thickness epidermal necrosis and detachment at the dermoepidermal junction, associated with lymphangiectasia and sparse chronic interstitial and perivascular inflammatory infiltrates, findings consistent with toxic epidermal necrolysis and supportive of the diagnosis.

 

Comment 2: Were the eyes involved? If yes, describe the ophthalmologic findings. If eyes were not involved please mention that they were not involved.

Response 2: We thank the Reviewer for highlighting this important aspect. The patient did have mild ocular involvement during the acute phase of TEN. We have now added a detailed description of the ophthalmologic findings and management in the Case Report section (page 3, line 109-114; page 5, line 165-167) and in the Discussion section (page 6, line 220-223).

 

Comment 3: What type of viral infection was the patient having? Were any viral cultures done to determine the type of viral infection?

Response 3: We appreciate the Reviewer’s comment. Viral testing performed at the referring hospital demonstrated positivity for Parvovirus B19 by PCR. No viral cultures were performed. We have added this information to the Case Report section (page 2, line 85-89). Although viral infection may have contributed to immune activation, application of the ALDEN algorithm supported the recently administered nonsteroidal anti-inflammatory drug as the most probable trigger for TEN.

 

Comment 4: Please explain why the authors did not perform the "mechanistic studies on skin or serum samples" in this child and how the pathophysiology interpretation relies on published data. Explain what is meant by mechanistic studies on skin or serum samples.

Response 4: We thank the Reviewer for requesting clarification. By “mechanistic studies,” we refer to investigations aimed at characterizing the biological pathways involved in TEN, including serum biomarker analyses (e.g., cytokines, granulysin, soluble Fas ligand), immunophenotyping of circulating immune cells, and immunohistochemical or molecular characterization of inflammatory pathways in skin biopsy specimens. These investigations were not part of routine clinical management at our institution and were therefore not performed during the acute phase of illness. We have revised the Discussion section to clarify this point (page 6-7, line 230-239). Consequently, our discussion regarding the potential mechanisms of action of IgM/IgA-enriched immunoglobulin, corticosteroids, cryopreserved human amniotic membrane, and fluorescent light energy is based on previously published experimental and clinical evidence rather than on patient-specific mechanistic data.

 

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The Authors have implemented the suggested comments and the article is now suitable for acceptance.

Reviewer 2 Report

Comments and Suggestions for Authors

Thanks for revising the manuscript based on reviewer's suggestions.