Bronchiolitis Obliterans in a Young Female Patient with Paraneoplastic Pemphigus Associated with Unicentric Castleman’s Disease

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Comments

The spelling of Castleman’s disease should be corrected in the title and the text.

In the opinion of the authors, the bronchiolitis obliterans was related to Castleman’s disease, or is it a coincidence? Did the patient have any constitutional symptoms? What was the reason for using tocilizumab? Do the patients need any further treatment for CD, eg, siltuximab?

The summary part should be a little more detailed, including a summary of CD, pemphigus, and bronchiolitis obliterans, their diagnosis, treatment possibilities, and differential diagnosis. How do these conditions relate to CD? The authors think that this was the leading cause of respiratory failure, or was there another reason to be considered? There are some case reports lately published with the same content, what is the novelty of this case presentation?

The bibliography needs to be formatted.  

Author Response

1. Comment: The spelling of Castleman’s disease should be corrected in the title and the text.
2. Reply: Thank you very much for this remark! Completely overlooked this mistake. 
3. Comment: In the opinion of the authors, the bronchiolitis obliterans was related to Castleman’s disease, or is it a coincidence? Did the patient have any constitutional symptoms? What was the reason for using tocilizumab? Do the patients need any further treatment for CD, eg, siltuximab?
4. Reply: Thank you again for your question. In our opinion, BO was related to Castleman's disease and in fact was part of the paraneoplastic syndrome associated with the disease, which we tried to highlight in this case report. Regarding Tocilizumab therapy that the patient received: it was primarily given to prevent chronic lung allograft dysfunction and modulation of alloimmune response after lung transplantation. Siltuximab is generally not recommended after surgical treatment of unicentric Castleman's disease. 
5. The summary part should be a little more detailed, including a summary of CD, pemphigus, and bronchiolitis obliterans, their diagnosis, treatment possibilities, and differential diagnosis. 
6. Reply: Thank you for your suggestion. By summary, I suppose you mean the discussion part. I think that the extensive description of CD in the first two paragraphs would suffice as a summary of the disease. As for the rest of the comment, the changes implemented to the Discussion have been marked in yellow.  
7. The authors think that this was the leading cause of respiratory failure, or was there another reason to be considered? There are some case reports lately published with the same content, what is the novelty of this case presentation?
8. Reply: 

   While previous reports describe the association of CD, PNP, and BO, our case has several novel aspects:

   • The young age (17 years) of the patient makes this an early presentation of the disease in a transitional phase. Most pediatric cases in literature had poor outcomes. 

   • The case highlights a successful bilateral lung transplantation after resection of UCD in a patient with end-stage BO, with sustained post-transplant survival beyond two years.

   • The detailed course and its complications—including the multidisciplinary management with ECMO support, abdominal surgery, and subsequent transplantation—offers a comprehensive therapeutic approach not extensively documented in previous literature.

   • Finally, our case underscores the importance of early recognition of this rare triad and the potential for favorable long-term outcomes despite its historically poor prognosis.

   • Comment: The bibliography needs to be formatted.  

   • Reply: Thank you for noting this. We have reformatted the reference list to conform to the journal’s (MDPI/Vancouver) style and verified one-to-one consistency between in-text citations and the bibliography.

Reviewer 2 Report

Comments and Suggestions for Authors

Manuscript entitled “Bronchiolitis Obliterans in a Young Female Patient with Paraneoplastic Pemphigus Associated with Unicentric Castleman’s Disease” by Kteiche W. et al.

This is a compelling, well-illustrated case that strings together three rare but tightly linked entities—unicentric Castleman’s disease (UCD), paraneoplastic pemphigus (PNP) and catastrophic bronchiolitis obliterans (BO)—successfully managed with tumour resection and subsequent bilateral lung transplantation. The report is valuable because only a handful of paediatric/young-adult UCD-PNP-BO cases culminating in transplantation have been documented.

Comments:

1. Since the first 14 lines of the Introduction restate Castleman's disease pathophysiology, which is then essentially restated in the Discussion, it should be revised to avoid repetition. A succinct summary of the illness, a list of current knowledge gaps, and a clear statement of the study's goal in the last sentence should instead be included in the updated Introduction.
2. Kindly indicate the kind of review. Include a specific Methods section outlining the database search strategy, inclusion/exclusion criteria, screening procedure, date of the most recent search, etc., if the review is systematic.
3. Please add a concise timeline figure presenting key clinical milestones in chronological order (relative to hospital admission), including onset of oral lesions, initiation and discontinuation of dapsone, FEV1 trajectory, timing of abdominal surgery, ECMO initiation, lung transplantation, and any changes in immunosuppressive therapy.
4. Please clarify the methodology used for autoantibody detection, including the specific ELISA kit, manufacturer, and positivity threshold. Additionally, elaborate on the temporal relationship between the appearance of envoplakin antibodies and the onset of bronchiolitis obliterans—was there serologic positivity preceding clinical manifestations?
5. Please include two additional sentences that provide context for the exclusion of infectious bronchiolitis, and provide evidence for the patient's unlikely immunotherapy-related bronchiolitis obliterans.
6. Please provide high-resolution CT and PET scan images and use arrows to clearly indicate the relevant pathological findings in Figure 2 and 3.
7. Histopathological images in Figures 4 and 5 are unclear. Please provide higher-resolution images at greater magnification, clearly indicate the key pathological features directly on the images (e.g., with arrows or annotations), and include properly labeled scale bars for reference.
8. The histopathological description lacks sufficient clarity.
9. Although tocilizumab is administered before liver transplantation, the reasoning behind this should be explained. Could you briefly clarify that the goal of IL-6 blockade was to lessen graft ischaemia–reperfusion injury and cytokine storm?
10. The therapeutic rationale and timing require clarification. Please specify the exact corticosteroid, dapsone, tocilizumab, and antifungal regimens used, including doses and durations. Additionally, provide a justification for the timing and sequencing of ECMO initiation relative to surgical resection, particularly why ECMO was preferred as an interim step rather than proceeding directly to operative management.
11. The post-operative course is under-reported. Complications such as bleeding, peritonitis, and renal failure are only briefly mentioned without specifying onset timing, management strategies, or clinical outcomes. Please expand this section to include detailed information on post-operative interventions, duration and intensity of ICU care, response to treatment, and overall recovery trajectory.
12. Only four transplant cases are cited; please expand the Discussion to acknowledge newer reports and trends. Consider adding a summary table that includes patient age, unicentric Castleman disease subtype, interval from diagnosis to liver transplantation, and post-transplant survival outcomes to contextualise the present case within the broader literature.
13. The abbreviation list is incomplete and several abbreviations are used without proper first-use definitions.

Author Response

Comment 1: Since the first 14 lines of the Introduction restate Castleman's disease pathophysiology, which is then essentially restated in the Discussion, it should be revised to avoid repetition. A succinct summary of the illness, a list of current knowledge gaps, and a clear statement of the study's goal in the last sentence should instead be included in the updated Introduction.

Reply 1: We thank the reviewer for this helpful comment. We have revised the Introduction to avoid repetition with the Discussion. The pathophysiology of Castleman’s disease is now presented only briefly, with a succinct summary of the illness. We have added a short section outlining current knowledge gaps, particularly concerning the association between unicentric Castleman’s disease, paraneoplastic pemphigus, and bronchiolitis obliterans. Finally, the last sentence of the Introduction now clearly states the aim of this case report.

Comment 2: Kindly indicate the kind of review. Include a specific Methods section outlining the database search strategy, inclusion/exclusion criteria, screening procedure, date of the most recent search, etc., if the review is systematic.

Reply 2: We thank the reviewer for this comment. We would like to clarify that the submitted manuscript is a case report, not a systematic review. Therefore, a Methods section outlining database search strategies, inclusion/exclusion criteria, or screening procedures is not applicable in this context. Instead, we have provided a detailed description of the patient’s presentation, diagnostic work-up, histopathological findings, treatment, and outcome, which represent the methodological framework of a case report.

Comment 3: Please add a concise timeline figure presenting key clinical milestones in chronological order (relative to hospital admission), including onset of oral lesions, initiation and discontinuation of dapsone, FEV1 trajectory, timing of abdominal surgery, ECMO initiation, lung transplantation, and any changes in immunosuppressive therapy.

Reply 3: We thank the reviewer for this helpful suggestion. In response, we have added a new figure (Figure 6) illustrating a concise timeline of the patient’s clinical milestones in chronological order relative to hospital admission. The figure summarizes the onset of oral lesions, initiation and discontinuation of dapsone, FEV1 decline, hospital admission, abdominal surgery, ECMO initiation, lung transplantation, subsequent immunosuppressive therapy, and follow-up. We believe this addition improves clarity and provides readers with a better overview of the clinical course.

Comment 4: Please clarify the methodology used for autoantibody detection, including the specific ELISA kit, manufacturer, and positivity threshold. Additionally, elaborate on the temporal relationship between the appearance of envoplakin antibodies and the onset of bronchiolitis obliterans—was there serologic positivity preceding clinical manifestations?

Reply 4: We thank the reviewer for this valuable comment. We have clarified in the revised manuscript that autoantibodies against envoplakin were detected using a commercially available ELISA kit (Euroimmun, Lübeck, Germany), with results considered positive according to the manufacturer’s recommended cutoff values. In our patient, envoplakin antibody positivity was confirmed at the time of diagnostic reassessment, coinciding with the onset of pulmonary manifestations rather than preceding them. This information has now been added to the Case Presentation section for clarity.

Comment 5: Please include two additional sentences that provide context for the exclusion of infectious bronchiolitis, and provide evidence for the patient's unlikely immunotherapy-related bronchiolitis obliterans.

Reply 5: We thank the reviewer for this insightful comment. In the revised manuscript, we have added clarifying sentences to the Discussion to indicate that infectious bronchiolitis was considered unlikely based on negative microbiological studies and absence of clinical or radiological evidence of acute infection. Furthermore, immunotherapy-related bronchiolitis obliterans was deemed unlikely, as the patient had not received immune checkpoint inhibitors or other targeted immunotherapies prior to the onset of respiratory symptoms.

Comment 6:  Please provide high-resolution CT and PET scan images and use arrows to clearly indicate the relevant pathological findings in Figure 2 and 3.

Reply 6: We thank the reviewer for this helpful suggestion. In the revised manuscript, we have replaced Figures 2 and 3 with high-resolution images. Arrows have been added to highlight the mosaic attenuation pattern on the HRCT (Figure 2) and the hypermetabolic right lower quadrant mass on the PET-CT (Figure 3), as recommended. We believe these modifications improve clarity and ensure that the relevant pathological findings are more readily identifiable.

Comment 7: Histopathological images in Figures 4 and 5 are unclear. Please provide higher-resolution images at greater magnification, clearly indicate the key pathological features directly on the images (e.g., with arrows or annotations), and include properly labeled scale bars for reference.

Reply 7: We thank the reviewer for this suggestion. Unfortunately, as this case occurred a few years ago, no additional material is available for re-analysis, and the original pathology samples have been disposed of according to institutional protocols. The involved pathologist is also no longer available for re-contact at the current time. Therefore, we are unable to provide new images beyond those already included in the manuscript. We believe the current figures adequately illustrate the key diagnostic findings relevant to this case.

Comment 8: The histopathological description lacks sufficient clarity.

Reply 8: We thank the reviewer for this helpful observation. In response, we have revised the description of the lung histopathology in the Case Presentation to provide greater clarity, specifying the fibrous obliteration of small bronchioles and the associated peribronchiolar lymphocytic inflammation (Figure 5). We believe this addition, together with the existing detailed description of the abdominal lesion and the annotated figures, now provides a clear and comprehensive account of the pathological findings.

Comment 9: Although tocilizumab is administered before liver transplantation, the reasoning behind this should be explained. Could you briefly clarify that the goal of IL-6 blockade was to lessen graft ischaemia–reperfusion injury and cytokine storm?

Reply 9: We thank the reviewer for this important comment. We would like to clarify that in our patient, tocilizumab, an IL-6 receptor monoclonal antibody, was administered prior to lung transplantation with the goal of significantly reducing dominant HLA antibodies in order to prevent antibody-mediated rejection. This approach is supported by recent evidence demonstrating the efficacy of IL-6 blockade in improving transplant outcomes through modulation of alloantibody responses (J Heart Lung Transplant. 2023 Jun;42(10):1353–1357. doi:10.1016/j.healun.2023.05.012). We have now included this clarification and reference in the revised manuscript.

Comment 10: The therapeutic rationale and timing require clarification. Please specify the exact corticosteroid, dapsone, tocilizumab, and antifungal regimens used, including doses and durations. Additionally, provide a justification for the timing and sequencing of ECMO initiation relative to surgical resection, particularly why ECMO was preferred as an interim step rather than proceeding directly to operative management.

Reply 10: 

We thank the reviewer for this detailed comment. As this is a case report, our intention is to focus on the clinical course and diagnostic challenges rather than provide exhaustive pharmacological regimens or treatment protocols. Therefore, we have summarized the immunosuppressive and antifungal therapies used without specifying every dose and duration, while emphasizing their role in the patient’s overall management.

Regarding the timing of ECMO initiation, we have clarified in the revised manuscript that veno-venous ECMO was instituted because the patient developed severe respiratory failure prior to abdominal surgery and prior to the availability of a suitable donor lung. ECMO was therefore required as a life-saving bridging measure until surgical resection and subsequent lung transplantation could be performed.

Comment 11: The post-operative course is under-reported. Complications such as bleeding, peritonitis, and renal failure are only briefly mentioned without specifying onset timing, management strategies, or clinical outcomes. Please expand this section to include detailed information on post-operative interventions, duration and intensity of ICU care, response to treatment, and overall recovery trajectory.

Reply 11: We thank the reviewer for this thoughtful comment. We agree that postoperative complications merit clarification. While a highly detailed account of every event would extend beyond the scope of a case report, we have revised the text to provide additional information regarding the onset, management, and outcomes of the key complications encountered. Specifically, we now describe the timing of bleeding, peritonitis, and renal failure, the main interventions applied, and the overall trajectory of ICU care and recovery. We believe this strikes a balance between completeness and readability while maintaining the case report’s focus on the rare and clinically significant association of Castleman’s disease, paraneoplastic pemphigus, and bronchiolitis obliterans.

Comment 12: Only four transplant cases are cited; please expand the Discussion to acknowledge newer reports and trends. Consider adding a summary table that includes patient age, unicentric Castleman disease subtype, interval from diagnosis to liver transplantation, and post-transplant survival outcomes to contextualise the present case within the broader literature.

Reply 12: We thank the reviewer for this constructive suggestion. We have expanded the Discussion to acknowledge newer reports and trends in transplantation for Castleman’s disease with paraneoplastic pemphigus and bronchiolitis obliterans. In addition, we have added Figure 7., which summarizes published cases/series (patient age, CD subtype, interval from diagnosis to transplantation, ECMO use, and outcomes) to contextualize the present case within the broader literature. Corresponding references have been added, and in-text citations updated accordingly.

Comment 13: The abbreviation list is incomplete and several abbreviations are used without proper first-use definitions.

Reply 13: Thank you for pointing this out. We performed a manuscript-wide audit of abbreviations. We now define all abbreviations at first use in the main text and have standardized nomenclature (e.g., HHV-8). We also updated the Abbreviations section to include all terms used in the manuscript and figure legends (see revised list below).

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have addressed all of my comments, and the manuscript can be accepted for publication.