A 55-year-old woman undergoes allogeneic hematopoietic stem cell transplantation from an HLA-matched, unrelated donor for treatment of acute myeloid leukemia. She received conditioning chemotherapy prior to the transplantation, and her immediate post-transplant course was uncomplicated. However, 3 weeks after the transplant, the patient develops worsening crampy abdominal pain and diarrhea. The diarrhea is watery and persistent, even at night, with output up to 3 liters daily. No particular food makes the symptoms better or worse. Medications include tacrolimus, prophylactic acyclovir, trimethoprim-sulfamethoxazole, and voriconazole. The patient has no other chronic medical conditions. She has been in the hospital since the transplantation and is on a low-microbial diet. Physical examination shows generalized maculopapular rash. Stool testing for Clostridioides (formerly Clostridium) difficile and PCR testing for cytomegalovirus are negative. Which of the following is the most likely cause of this patient's diarrhea?

Question

A 55-year-old woman undergoes allogeneic hematopoietic stem cell transplantation from an HLA-matched, unrelated donor for treatment of acute myeloid leukemia.  She received conditioning chemotherapy prior to the transplantation, and her immediate post-transplant course was uncomplicated.  However, 3 weeks after the transplant, the patient develops worsening crampy abdominal pain and diarrhea.  The diarrhea is watery and persistent, even at night, with output up to 3 liters daily.  No particular food makes the symptoms better or worse.  Medications include tacrolimus, prophylactic acyclovir, trimethoprim-sulfamethoxazole, and voriconazole.  The patient has no other chronic medical conditions.  She has been in the hospital since the transplantation and is on a low-microbial diet.  Physical examination shows generalized maculopapular rash.  Stool testing for Clostridioides (formerly Clostridium) difficile and PCR testing for cytomegalovirus are negative.  Which of the following is the most likely cause of this patient's diarrhea?

Quizplus · Accepted Answer

Explanation: This patient's profuse, watery diarrhea and maculopapular rash raise strong suspicion for acute graft-versus-host disease (GVHD), an immune-mediated, multisystem inflammatory condition that occurs in 35%-50% of patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT). Acute GVHD arises when donor T cells (particularly cytotoxic T cells) identify antigens on host epithelial cells as foreign and subsequently generate a strong proinflammatory response. Patients with acute GVHD generally develop symptoms within 100 days of transplantation, including the following: Maculopapular rash that is often painful and can become confluent (resembling Stevens-Johnson syndrome) Profuse, watery diarrhea that has a secretory pattern (eg, persistent, unrelated to eating, occurs at night) and is often associated with crampy abdominal pain, nausea, and vomiting Liver inflammation with damage to the biliary tract epithelium, leading to elevated bilirubin, alkaline phosphatase, and transaminases Acute GVHD is usually diagnosed by biopsy (eg, colonoscopy with biopsy) after common infections such as Clostridioides difficile and cytomegalovirus are ruled out. Glucocorticoids are the mainstay of therapy. (Choice A) GVHD is almost entirely mediated by T cells; studies have found that removal of donor T cells almost completely eliminates the risk of GVHD (but increases the risk of graft rejection and disease recurrence). B cells and the humoral antibody response play a small role in the pathogenesis of GVHD. A classic example of antibody-dependent cellular cytotoxicity is natural killer cell activation by antibodies (which is used in some forms of cancer immunotherapy). (Choice C) Cryptosporidiosis is a common cause of profuse secretory diarrhea and most often manifests in those with impaired cellular or humoral immunity. However, a maculopapular rash would be atypical, and this patient, who has been hospitalized since transplant and has been eating a low-microbial diet, is at a lower risk. (Choice D) Conditioning chemotherapy is administered prior to transplantation to destroy active immune cells (immunoablative) or to destroy hematopoietic stem cells in the bone marrow to create room for transplanted stem cells (myeloablative). Although chemotherapy is often associated with a few days of nausea and vomiting, gastrointestinal side effects generally resolve within a week; symptoms 3 weeks later would be very atypical. (Choice E) Patients who undergo solid organ or HSCT are at increased risk for lymphoproliferative disorders. Most cases present many years (not weeks) after transplantation with extranodal or CNS lesions. Profuse watery diarrhea and a maculopapular rash would be atypical. Educational objective: Acute graft-versus-host disease is a common complication of allogenic hematopoietic stem cell transplantation. It arises when donor T-lymphocytes recognize antigens on host epithelial cells as foreign and initiate a strong inflammatory response. Patients usually manifest symptoms within 100 days of transplant, including a maculopapular rash; profuse, watery diarrhea; and signs of hepatobiliary inflammation.

A 55-Year-Old Woman Undergoes Allogeneic Hematopoietic Stem Cell Transplantation from an HLA-Matched