Surgical Treatment of Severe Bowel Obstruction as a Rare Complication Following Allogenic Hematopoietic Stem Cell Transplantation

Round 1

Reviewer 1 Report

The text is well written and the English language is adequate.

This case reports the evolution and outcome of a patient suffering from MDS and undergoing a transplant then complicated by steroid-resistant GVHD and histologically documented colitis linked to CMV. The immunosuppressive therapy administered consisted of steroids, budesonide and ECP. Evidence from the literature shows that infliximab, but also other monoclonal antibodies, can be used in gastrointestinal GvHD. - Journal of Pediatric Hematology / Oncology: June 2009 - Volume 31 - Issue 6 - p 456-461 doi: 10.1097 / MPH.0b013e31819daf60, Curr Treat Options Gastroenterol. 2005 Jun; 8 (3): 249-258. doi: 10.1007 / s11938-005-0017-9.PMID: 15913514. Can the authors explain why these drugs were not used? In the discussion of the clinical case these drugs should at least be mentioned.

Author Response

 

We are grateful for these comments regarding our present manuscript. We recognized the role of emerging therapy in steroid refractory GVHD, and monoclonal antibodies like infliximab and vedolizumab have been reported used with successfully outcome in this patient group, although the documentation are limited. In general, these antibodies are not recommended used in the presence of CMV activation as present in our patient, and hence we did not use it. However, we have added this in our description, and in the discussion of this case. The mention references are cited.

Reviewer 2 Report

SOME GENERAL COMMENTS:

- Introduction could be essentially condensed. The readers who are interested to read this article are familiar with the background of allotransplants.

- The pre-transplant course of the patient could be condensed as well. The focus of this case report is in the post-transplant course.

- The differential diagnosis between acute intestinal GVHD and intestinal CMV should be discussed more thoroughly – it is the main issue in this case (see below).

SOME SPECIFIC COMMENTS:

• In this case, CMV enteritis should be termed as CMV disease (not CMV infection) which is still a potentially fatal complication of allotransplant.
• In the discussion Glucksberg's grading is mentioned but not the grade of the patient; it should be given.
• Line 101: valganciclovir instead of valaciclovir? 
• Figure 1 is informative. However, in addition to surgery, also colonoscopies should be added (and post-transplant course should be clarified in the text).
• Intestinal aGVHD had the onset d+52, and was verified by colonoscopy and biopsies (CT-scan could have been useful to see extensiveness of aGVHD), and treated by steroid with a good response. Typically, after starting steroid treatment, CMV-PCR turned to positive, and ganciclovir was started. Obviously the patient had no GI symptoms at this time.
• Abdominal pain developed few weeks later (d+?; lines 93-94; should be clarified), obviously at the time-point when ECP treatments were initiated, and biopsies revealed both aGVHD and CMV in the intestine? It is well known that CMV disease in the intestine can mimic aGVHD, and the differential diagnosis is difficult, both conditions may also exist concurrently.
• GI-GHVD is often limited in terminal ileum as shown here by CT-scan, and sometimes a local fibrotic stenosis, though rare, develops and is an unavoidable indication for surgery as was the case here d+250, 8 months post-transplant and 3-4 months (?, should be clarified) after suggested reactivation of intestinal GVHD and CMV disease.
• Timelines of the post-transplant course should be more clear. If the patient has overt intestinal GVHD and CMV disease over 3 to 4 months, he probably gets increasingly other problems as bacterial and fungal infections, and is not fit for the surgery.
• It is not probable that intestinal GVHD, even if restricted, could be treated surgically as GVHD often emerges in the adjacent areas of intestine. This is strange and gives the reader an impression about the main role of CMV in this case? This is why the differential diagnosis between these two alternatives should be handled in the discussion, and furthermore the facts for the aGVHD as the main causative factor should be more convincing.
• Surgery was done 8 months post-transplant when it is certainly safer than within first months post-transplant when patients are more immunocompromised, but I would hesitate to state that post-transplant intestinal surgery is safe and well tolerated. Later in the course of transplant period surgery could possibly be feasible assuming that infection and other problems are in control.

 

Author Response

SOME GENERAL COMMENTS:

- Introduction could be essentially condensed. The readers who are interested to read this article are familiar with the background of allotransplants.

Based on this comment, we have reduced the length of the introduction, and making it more “to the point”.

- The pre-transplant course of the patient could be condensed as well. The focus of this case report is in the post-transplant course.

Although we believe some of the background regarding the patient history is important for understanding the whole picture, we agree that some points could be shortened, and hence we have reduced some part of the pre-transplant course.

- The differential diagnosis between acute intestinal GVHD and intestinal CMV should be discussed more thoroughly – it is the main issue in this case (see below).

This is an important point, and accordingly we have strengthened the discussion of this part of the history.

SOME SPECIFIC COMMENTS:

• In this case, CMV enteritis should be termed as CMV disease (not CMV infection) which is still a potentially fatal complication of allotransplant.

We agree in this point, and accordingly we have changed this to CMV disease.

• In the discussion Glucksberg's grading is mentioned but not the grade of the patient; it should be given.

Accordingly, we have further precisely the grading system according to Glucksberg score.

• Line 101: valganciclovir instead of valaciclovir? 

This is altered.

• Figure 1 is informative. However, in addition to surgery, also colonoscopies should be added (and post-transplant course should be clarified in the text).

We have also marked coloscopy examinations and ultrasound examination, and clarified this in the patient’s history.

• Intestinal aGVHD had the onset d+52, and was verified by colonoscopy and biopsies (CT-scan could have been useful to see extensiveness of aGVHD), and treated by steroid with a good response. Typically, after starting steroid treatment, CMV-PCR turned to positive, and ganciclovir was started. Obviously, the patient had no GI symptoms at this time.

We have specified the clinical course more clearly in our revised version of the paper.

• Abdominal pain developed few weeks later (d+?; lines 93-94; should be clarified), obviously at the time-point when ECP treatments were initiated, and biopsies revealed both aGVHD and CMV in the intestine? It is well known that CMV disease in the intestine can mimic aGVHD, and the differential diagnosis is difficult, both conditions may also exist concurrently.

We agree in this point, which is an important clarification, we have utterly specified this in our revised version of the manuscript.

• GI-GHVD is often limited in terminal ileum as shown here by CT-scan, and sometimes a local fibrotic stenosis, though rare, develops and is an unavoidable indication for surgery as was the case here d+250, 8 months post-transplant and 3-4 months (?, should be clarified) after suggested reactivation of intestinal GVHD and CMV disease.

We have utterly clarified this time aspects in our present history.

• Timelines of the post-transplant course should be more clear. If the patient has overt intestinal GVHD and CMV disease over 3 to 4 months, he probably gets increasingly other problems as bacterial and fungal infections, and is not fit for the surgery.

This point is important, we try to keep the immunosuppressive burden as low as possible as we regarded the stenotic/fibrotic part of is intestinal disease as refractory to further systemic treatment. Hence, we reduced the risk of opportunistic infections, we have specified this in our present paper.

• It is not probable that intestinal GVHD, even if restricted, could be treated surgically as GVHD often emerges in the adjacent areas of intestine. This is strange and gives the reader an impression about the main role of CMV in this case? This is why the differential diagnosis between these two alternatives should be handled in the discussion, and furthermore the facts for the aGVHD as the main causative factor should be more convincing.

In this case, it is obvious to believe that both GVHD and CMV contributed to the severe gastrolienal pathology, and hence we strength the discussion of concomitant CMV and GVHD.

• Surgery was done 8 months post-transplant when it is certainly safer than within first months post-transplant when patients are more immunocompromised, but I would hesitate to state that post-transplant intestinal surgery is safe and well tolerated. Later in the course of transplant period surgery could possibly be feasible assuming that infection and other problems are in control.

This is an important point from the reviewer, and we agree that general conclusion of course should not be based on case reports alone. Accordingly, we have modified these statements, and are more cautiously int our revised version of the manuscript.

Reviewer 3 Report

The case is original, abdominal surgeries for post HSCT complications are rarely described in the literature. There is the patient's consent.

The title describes the core message of the case and the abstract incorporates the core key message with necessary detail in a concise manner.

Case description- minor comments:

• The case is well described, with fine imagining and histopathological images;
• Line 73 – methotrexate on days 1, 4 and 7! Maybe the authors want to say days 1,3 and 6, this is the standard treatment
• How long was the treatment for GVHD and CMV? There was any other signs of GVHD after surgery? you can ad some details for evolution in time

 

In conclusion, this case report may stimulate the generation of new treatment for specific situations (Concurrent CMV disease and gut GVHD is a really a challenging situation) and thus may support a new research.

 

Author Response

The case is original, abdominal surgeries for post HSCT complications are rarely described in the literature. There is the patient's consent.

Patient consent is submitted to the editorial staff, as kept confidential.

The title describes the core message of the case and the abstract incorporates the core key message with necessary detail in a concise manner.

Case description- minor comments:

• The case is well described, with fine imagining and histopathological images;

We are grateful for this comment.

• Line 73 – methotrexate on days 1, 4 and 7! Maybe the authors want to say days 1,3 and 6, this is the standard treatment

Accordingly, this altered has day 1,4 and 6 is correct.

• How long was the treatment for GVHD and CMV? There was any other signs of GVHD after surgery? you can ad some details for evolution in t

We appreciate this, comment. And we have further discussed these features, as also stated in Figure 1.

 

In conclusion, this case report may stimulate the generation of new treatment for specific situations (Concurrent CMV disease and gut GVHD is a really a challenging situation) and thus may support a new research.

Thanks for this comment, we added a comment that further research is needed to study the possibilities of surgery in these rare cases of stenotic gastrointestinal complications following allo-HSCT.