Gastrointestinal Graft-Versus-Host Disease

Gastrointestinal graft-versus-host disease is immune mediated injury of the gut by donor T cells after allogeneic haematopoietic stem cell transplantation. It is a major cause of morbidity and non-relapse mortality.

Acute graft-versus-host disease develops in 30% to 60% of recipients of allogeneic transplants, and the gut is involved in about half. Chronic graft-versus-host disease occurs in 30% to 70% and may involve the oesophagus and gut. Steroid refractory gut disease has a 6-month survival of about 30% to 50%.

Pathophysiology.

Donor T cells recognise host antigens presented after conditioning related injury and gut barrier breakdown, releasing cytokines and causing crypt cell apoptosis, mucosal denudation and loss of intestinal stem cells.

Secretory diarrhoea (volume graded by stool output), nausea, vomiting, anorexia, crampy abdominal pain, gastrointestinal bleeding, and protein losing enteropathy. Skin rash and cholestatic liver disease often coexist. Chronic disease causes dysphagia, oesophageal webs, weight loss and malabsorption.

Red flags.

• Stool output over 1,500 mL daily.
• Ileus or severe pain.
• Gastrointestinal bleeding.
• Fever or sepsis.

Exclude infection: stool tests for Clostridioides difficile, norovirus, adenovirus, rotavirus and cytomegalovirus, with bacterial and parasitic cultures. Endoscopy with biopsies from stomach, duodenum and colon (apoptotic crypt cells, crypt drop out) confirms the diagnosis, and tests for cytomegalovirus by immunostaining. CT shows bowel wall thickening and ileus. Stage by daily stool volume and presence of rash and bilirubin (stage 1 to 4).

Differential diagnosis.

• Cytomegalovirus, adenovirus and Clostridioides difficile colitis.
• Conditioning related mucositis.
• Drug toxicity (mycophenolate mofetil).
• Thrombotic microangiopathy.
• Neutropenic enterocolitis.

Give systemic corticosteroids with continued immunosuppression, and add a second agent for steroid refractory disease. Supportive care includes fluids, electrolyte replacement, nutrition and infection prophylaxis.

• Methylprednisolone: 1 to 2 mg/kg IV daily (usually 2 mg/kg daily divided every 12 hours) for 7 to 14 days, then prednisolone orally with taper over 6 to 8 weeks once stool volume is under 500 mL daily; maximum 2 mg/kg daily; monitor glucose, blood pressure, infection and bone health; reduce in older adults and give gastric protection.
• Budesonide (adjunct for mild gut disease): 9 mg orally once daily in the morning for 4 to 8 weeks, then taper; maximum 9 mg daily; monitor for adrenal suppression and infection; reduce in hepatic impairment.
• Ruxolitinib (steroid refractory): 5 mg orally twice daily, increased to 10 mg twice daily if blood counts allow; maximum 20 mg daily; monitor blood counts, infection (including cytomegalovirus reactivation) and bleeding; reduce to 5 mg twice daily with strong CYP3A4 inhibitors, and in severe renal or hepatic impairment (5 mg once daily).
• Co-trimoxazole (prophylaxis against Pneumocystis): 480 mg orally once daily on 3 days each week; maximum 960 mg daily; monitor blood counts, potassium and creatinine; halve the dose when creatinine clearance is 15 to 30 mL/min.

Add antiviral treatment for cytomegalovirus, ganciclovir 5 mg/kg IV every 12 hours (reduce in renal impairment), when disease is confirmed.

Monitoring. Daily stool volume, weight and electrolytes during treatment; blood counts weekly; repeat endoscopy for non-response.

Referral and escalation. Haematology transplant team; gastroenterology; infectious disease; critical care for sepsis.

Special groups. Children need weight based dosing.