Paradox inflammatory reaction such as appendicitis epiploica and diverticulitis of the sigmoid colon under ongoing immunosuppression after previous liver transplantation (LTx)

Abstract Objective Inflammatory reactions caused by immunosuppression appear a particular interesting disease due to its very specific and partly unclear etiopathogenesis. Based on clinical case-specific management experiences and selective references from the literature, the rare case of an acute intraabdominal inflammation as unusual complication or side effect (at the gastrointestinal [GI] tract) of the ongoing immunosuppressive medication using Mycophenolate mofetil and Tacrolimus after previous liver transplantation is to be illustrated. Case presentation Medical history (hx): 1) Current: A 68-years old male patient underwent abdominal CT scan because of pain in the left lower abdomen with the suspicious diagnosis of diverticulitis leading to initiation of antibiotic therapy 24 h prior to the transferral to the own hospital for adequate liver transplantation (LTx) follow-up investigation. 2) Medication contained Sitagliptin 1 × 100 mg, Omeprazol 1 × 40 mg, Mesalazin 500 mg 3 × 2, Movicol 1 (on demand), Mycophenolate mofetil 2 × 500 mg, Tacrolimus 2 × 1 mg and Hydrochlorothiazid 1 × 2.5 mg. 3) Additional diagnoses included arterial hypertension, diabetes mellitus and urinary bladder diverticle. 4) Previous surgical intervention profile comprises resection of liver segments IV/V due to HCC (2011), orthotopic liver transplantation because of HCC caused by alcohol-induced liver cirrhosis (2013) and an intervertebral disc operation (2018). Physical examination of the abdomen revealed marked tenderness in the lower left quadrant. The abdominal wall was soft and there were no defensive tension and no peritonism. The patient was in good general condition and nutritional status. He was cardiopulmonarily stable and oriented to all qualities. Diagnostic measures showed a CRP of 38.0 (normal range, < 5) mg/L and a white blood cell count within normal range. Leading diagnoses were found using abdominal CT scan, which demonstrated an extended diverticulosis and an appendicitis epiploica within the immediate subperitoneal region of the left lower abdomen with an oval fat isodense structure in the region of the sigmoid colon with surrounding inflammatory imbibition and pronounced intestinal wall. Suspicious diagnosis was the 1st episode of an uncomplicated diverticulitis of the sigmoid colon associated with an appendicitis epiploica. Therapeutic approach was given by conservative therapy with infusion therapy, analgesia as well as inital “n. p. o.” and following initiation of oral nutrition. In addition, calculated antibiotic therapy with Cefuroxime and Clont was initiated. Clinical course was uneventful, with discharge on the eighth day of hospital stay with no pathological findings and substantial improvement in clinical and laboratory findings. Further advice consisted of clinical and laboratory follow-up control investigations by the family practitioner and nutritional counselling. In addition, a colonoscopy should be performed within four months. Conclusions The described case i) is either one of the many side effects of the immunosuppressive medication Mycophenolate mofetil and Tacrolimus listed as “colonic inflammation” and “gastrointestinal inflammation”, respectively, or ii) can be considered an inflammatory response of a susceptible (gastro-)intestinal mucosa or the whole intestinal wall to microbes or microbial particles or agents caused by transplantation-associated immunosuppressive medication.

I.) First reviewer's recommendation was: It would be better to use the names of the active substances of the drug and not the trade namens.Right now it is mixed.RESPONSE: The authors followed the reviewer's instruction -see the text: In particular, from "Januvia" to "Sitagliptin", from "Salofalk" to "Mesalazin", from "Pantozol" to "Omeprazol" and from "Delix" to "Hydrochlorothiazid" (see also "Abstract" and "Case report" section).

II.)
The reviewer wondered: The role of ultrasound as a diagnostic tool in divertikulitis is not mentioned unfortunately.

RESPONSE:
The reviewer is basically right.However, a sufficient ultrasound-based investigation of the colon predicts developed expertise.In addition, abdominal ultrasound is considered and established a basic diagnostic tool in case of diagnostic need for the suspicious diagnosis "unclear abdomen" or even "acute abdomen".
The authors solved it (to add "ultrasound" in the text -"Discussion" section) as follows: " ... and pronounced intestinal wall.
However, abdominal ultrasound might have also helped appropriately -it is considered and established a basic diagnostic tool in case of diagnostic need for the suspicious diagnosis of "unclear abdomen" or even "acute abdomen" but in experienced hands since a sufficient ultrasound-based investigation of the colon predicts developed expertise.
The appendices epiploicae are ... " III.)The reviewer's question was: It is written, that antibiotics are administered in sigma-diverticulitis Type I-IIc but according to the S3-guideline antibiotic therapy is not always required for Type I a/b.

RESPONSE:
The reviewer is right -to address this aspect, the authors added the following phrase int the Text of the ""Discussion" section: " ... sigmoid diverticulitis in stage I-IIc, an antibiotic therapy is also administered (in particular, due to additional risk factors such as the status after organ transplantation and ongoing immunosuppressive medication despite the fact that no antibitoiucs are usually needed in stage I according to the S3 guidelines), which is often not needed in the treatment of appendicitis epiploicae ... " IV.) The reviewer suggested: And optionally: Maybe a the role of the microbiome and possible changes under immuno supressive therapie can be addressed in the discussion.Data are very sparse.RESPONSE: Thanks for this treasonable aspect, which need to be added -as follows at the end of the "Discussion" section: " … more important and should be further discussed.
Last but not least, the role of the microbiome in a susceptible mucosa characterized by possible changes under immunosuppressive therapy, in particular, an altered immunoreactivity and immune response even at the very local site need to be considered in this complex etiopathogenesis.However, data are very sparse.

Conclusion
The case presented ... " Reviewer 2: 1.The reviewer stated: Authors present a case report on a subject that the surgical community should be aware of, and which is worth being published.
To improve the work, I would like to remark the following: Authors could explain a little more clearer why they are sure diverticulitis is induced by immunosuppression in this case-diverticulitis might have also occurred accidentally in a 68-year old person.

RESPONSE:
The reviewer is completely right -there is also the option that "diverticulitis might have also occurred accidentally in a 68-year old person" (however, in case of ongoing immunosuppressive medication).
And, no, the authors are not sure that diverticulitis is induced by immunosuppression in this case -it is a possible option of etiopathogenesis the authors want to suggest.

" ... Conclusion
The case presented is either one of several side effects of Mycophenolate mofetil and/or Tacrolimus listed in the package insert as "colonic inflammation" or "gastrointestinal inflammation", or a described inflammatory reaction of a susceptible (gastro)intestinal mucosa or entire intestinal wall to microbes or microbial particles or agents caused by the transplantation-related immunosuppressive medication.However, diverticulitis might have also occurred accidentally in a 68-year old patient...." 2. The reviewer recommended: Conclusion could be shortened and the crucial points of the take-home message should be worked out more clearly.What is the one-sentence take-home message of this work?RESPONSE: The authors followed the reviewer's suggestion and shortened the "Conclusion" section by 50 % (see above) emphasizing the first paragraph coming very close to the reviewer's specific orientation onto a "one-sentence take-home message of this work".

Reviewers' Comments to Revised Submission
All my comments and suggestions were implemented to my full satisfaction.I recommend acceptance in the present form.