Intravenous Liposomal Amphotericin B for Complicated Pediatric Cutaneous Leishmaniasis: A Case Series

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

comments in word text

Comments for author File: Comments.pdf

Author Response

Dear Reviewer,

We thank you for your thorough review and valuable comments on our manuscript entitled:
“Intravenous Liposomal Amphotericin B for Complicated Pediatric Cutaneous Leishmaniasis: A Case Series.” We appreciate the constructive feedback provided by the reviewers and have carefully addressed each of your comments.

Reviewer Comments (From attached PDF)

This is an interesting and valuable case series on leishmaniasis entitled:

“Intravenous Liposomal Amphotericin B for Complicated Pediatric Cutaneous

Leishmaniasis: A Case Series.” The manuscript provides sufficient information, and the topic is appropriate for the journal.

We thank the reveiwer.

Introduction section (lines 42–44): Add more information about Leishmania virulence, species, and clinical importance.

Done. The paragarph now reads: “In addition to L. major, L. tropica is also present in Israel. Species-specific virulence factors, such as lipophosphoglycan (LPG) and GP63 protease, contribute to immune evasion and lesion severity. The clinical relevance lies in the risk of prolonged ulceration, scarring, and psychosocial impact, especially in children.

Formatting issue (lines 56–60): Text appears in a different font style/size.
Done. We appologize for this technical issue.

 

Table 2: Add footnotes for reference ranges and abbreviations such as AST/ALT.
Done.

 Final sections (lines 311–317) are missing: Author Contributions, Funding, IRB Statement, Informed Consent, Data Availability, Conflicts of Interest.
Done.These sections have now been added at the end of the manuscript to comply with journal requirements.

 

Sincerely,
Moshe Shmueli, MPH
Faculty of Health Sciences
Ben-Gurion University of the Negev
Beer-Sheva 84101, Israel
Email: mosheshm@post.bgu.ac.il
Tel: +972-50-6667882

Reviewer 2 Report

Comments and Suggestions for Authors

The paper present a clinically relevant retrospective case series evaluating the use of intravenous liposomal amphotericin B (L-AmB) for complicated cutaneous leishmaniasis (CL) in children. The manuscript addresses a gap in the literature concerning pediatric patients with facial or multiple lesions. It offers insights into treatment response and safety outcomes. The study contributes to the evolving discussion around second- and third-line therapies for CL in resource-accessible settings.

 

Remarks

 

The scientific rigor of the study is limited by the absence of statistical analysis. Although detailed descriptive data are presented, they rely solely on proportions and means without applying inferential statistics to assess treatment efficacy or adverse event patterns. Given the structured collection of pre- and post-treatment clinical and laboratory data, basic statistical tests, like paired t-tests for laboratory trends and Fisher’s exact tests for categorical outcomes, could have been applied to strengthen the conclusions.

 

The study’s definition of therapeutic success, based purely on subjective clinical observation without microbiologic confirmation, weakens its internal validity. While the discussion accurately reflects the reported results and acknowledges important limitations, some interpretations (e.g., the characterization of adverse events as “manageable”) may understate the clinical impact, particularly given that 15% of patients required temporary discontinuation. Incorporating even simple inferential statistics and more standardized outcome definitions would have significantly enhanced the credibility and generalizability of the findings.

 

The absence of a control or comparator group prevents attribution of observed improvements directly to the intervention. The outcome measures relied entirely on subjective clinical assessment without the use of standardized scoring tools, and microbiological confirmation of cure via PCR was not performed post-treatment, both of which limit the reliability of the efficacy assessment.

 

Safety reporting lacks granularity; it is unclear since severity grading is not provided.

 

The broad follow-up window (30 to 90 days) introduces heterogeneity in outcome assessment timing, potentially obscuring differences in healing progression.

 

Although a wide range of demographic and clinical variables were collected, no subgroup or stratified analyses were conducted to explore associations with treatment response or adverse events.

 

Other Remarks

The sentence "While contact between these populations is limited, both groups have equal access to the national healthcare system. Medical insurance for children in Israel is universal and fully subsidized." does not contribute meaningfully to the study’s objectives or outcomes. The paper does not examine differences in healthcare access, treatment adherence, or outcomes between ethnic groups. Therefore this sociopolitical commentary is unnecessary and may distract from the scientific focus. I recommend removing these sentences to maintain clarity and relevance within the clinical context of the manuscript.

 

Minor Remarks

 

The manuscript contains numerous typographical, grammatical, and formatting issues that require careful revision.

 

In addition, commas are frequently placed incorrectly before in-text citations.

Author Response

Dear Reviewer,

We thank you for your thorough review and valuable comments on our manuscript entitled:
“Intravenous Liposomal Amphotericin B for Complicated Pediatric Cutaneous Leishmaniasis: A Case Series.” We appreciate the constructive feedback provided by the reviewers and have carefully addressed each of your comments.

Reviewer  Comments：

The scientific rigor of the study is limited by the absence of statistical analysis. Although detailed descriptive data are presented, they rely solely on proportions and means without applying inferential statistics to assess treatment efficacy or adverse event patterns. Given the structured collection of pre- and post-treatment clinical and laboratory data, basic statistical tests, like paired t-tests for laboratory trends and Fisher’s exact tests for categorical outcomes, could have been applied to strengthen the conclusions.
Thank you for this important comment. As we noted, this is a case series which, although relatively large compared to the existing literature, is still small in terms of statistical power for robust inferential analyses. Nevertheless, following the reviewer’s suggestion, we performed a sub-analysis stratified by groups, focusing on reduction in ulceration, decrease in lesion size, and substantial clinical improvement, in order to identify potential trends or notable differences between groups. For this revision, we have included an additional document presenting supplementary Tables 1-3 with these comparisons.

We adressed these important issues in the Results section; “..Patients who showed ulcer size reduction after 10 days had significantly larger cysts compared to those whose cysts were smaller.(Supplementary table 1)”

“The demographic, clinical and lesion characteristics did not differ significantly between children with or without ulcer reduction, lesion size reduction or substantial healing ( Supplementary tables 1-3).”

The definition of therapeutic success is based purely on subjective clinical observation without microbiologic confirmation.
We appreciate the reviewer’s important observation and acknowledge the limitation. As noted, our definition of therapeutic success was based on clinical assessment rather than microbiological confirmation. We have addressed this limitation explicitly in the revised Discussion section.

While we recognize that aesthetic and surface-level improvement does not necessarily equate to full microbiologic cure, our evaluation focused on the observable resolution of lesions, which is the standard and practical approach in real-world clinical settings where follow-up invasive sampling is often not feasible. We agree that the absence of post-treatment PCR or culture limits the ability to definitively confirm parasitological clearance, and we have now emphasized this point more clearly in the discussion to avoid overstatement of efficacy.

The appropriate paragraph at discussion reads: “...Importantly, our assessment was based solely on clinical observation, without microbiologic confirmation of parasite eradication. Therefore, we do not claim microbiological cure, but rather substantial clinical improvement, as defined by the treating physician and the patient care giver. Scarring, although common, did not preclude the classification of treatment success. The literature remains inconsistent in defining treatment response in CL, with distinctions often blurred between microbiologic healing and cosmetic resolution.(14,32,33) Our study shows that although L-AmB leads to significant clinical improvement, aesthetic recovery is often incomplete, especially in cases with deep or extensive lesions.”

Some interpretations, such as calling adverse events "manageable," may understate clinical impact.

 We have revised the language to better reflect the clinical impact of adverse events. The sentence now reads ; “While not devoid of side effects, most adverse events were reversible and addressed with temporary treatment adjustments; however, some required close monitoring and clinical intervention.”

The absence of a control or comparator group prevents attribution of improvement to the intervention.
We acknowledge this important limitation. These cases were complex and uncommon, often involving facial or multiple lesions and prior treatment failures, which made finding matched controls difficult. Although causal inference is limited, we focused on within-patient pre and post treatment comparisons to provide meaningful clinical insight. This point is now emphasized in the revised Discussion.

Outcome measures relied on subjective assessment without standardized scoring tools or microbiologic cure confirmation.

We recognize how subjective assessment can create bias. To ensure a standardized assessment, to the best of our ability,  we based evaluations exclusively on expert infectious disease specialists and dermatologists, all working at a regional center with extensive patient experience. Additionally, we detailed recovery using specific parameters to create standardization, including: crust falling or reduced ulceration, appearance of scarring, lesion size reduction, reduced induration, pigmentation changes, and substantial healing—each reported with corresponding counts and percentages.

Safety reporting lacks granularity; no severity grading was provided.

We agree with this comment, and adjusted our limitations accordingly. The sentence now reads: “Some data may have been incompletely recorded, and outcomes were based on clinical assessment without standardized scoring, safety grading score or parasitologic cure confirmation.”

The broad follow-up window (30 to 90 days) may obscure healing progression differences.
To demonstrate that the differences in healing progression are not ambiguous, we have now clarified the mean and standard deviation of the follow-up period. The revised sentence in the Results section reads: “At the second two follow-up visits, occurring between 30 to 90, (mean ± SD: 38.5 ± 17.84) days after treatment initiation, 96% (n=23) showed continued improvement in terms of crust resolution and lesion size reduction.”

No subgroup or stratified analyses were conducted despite the wide range of variables collected.

In the attached file (Supplementery Tables 1-3), we performed stratified subgroup analyses comparing patients with and without substantial healing, lesion size reduction, and ulceration reduction. We recognize that, despite being relatively large for this field, the sample size remains limited for robust statistical inference.

Sociopolitical commentary on healthcare access should be removed for relevance and clarity.

Done.

Minor Comment: Numerous typographical, grammatical, and formatting issues.
Response:
We have carefully reviewed and corrected all identified typographical, grammatical, and formatting errors throughout the manuscript.

Minor Comment: Commas are incorrectly placed before in-text citations.
Done.

We hope that the revisions meet your expectations and improve the quality and clarity of our work. We thank you again for your constructive feedback.

Sincerely,
Moshe Shmueli, MPH
Faculty of Health Sciences
Ben-Gurion University of the Negev
Beer-Sheva 84101, Israel
Email: mosheshm@post.bgu.ac.il
Tel: +972-50-6667882