Acute graft-versus-host disease of the gut: considerations for the gastroenterologist

Abstract

Haematopoietic stem cell transplantation (HSCT) is central to the management of many haematological disorders. A frequent complication of HSCT is acute graft-versus-host disease (GVHD), a condition in which immune cells from the donor attack healthy recipient tissues. The gastrointestinal system is among the most common sites affected by acute GVHD, and severe manifestations of acute GVHD of the gut portends a poor prognosis in patients after HSCT. Acute GVHD of the gastrointestinal tract presents both diagnostic and therapeutic challenges. Although the clinical manifestations are nonspecific and overlap with those of infection and drug toxicity, diagnosis is ultimately based on clinical criteria. As reliable serum biomarkers have not yet been validated outside of clinical trials, endoscopic and histopathological evaluation continue to be utilized in diagnosis. Once a diagnosis of gastrointestinal acute GVHD is established, therapy with systemic corticosteroids is typically initiated, and non-responders can be treated with a wide range of second-line therapies. In addition to treating the underlying disease, the management of complications including profuse diarrhoea, severe malnutrition and gastrointestinal bleeding is paramount. In this Review, we discuss strategies for the diagnosis and management of acute GVHD of the gastrointestinal tract as they pertain to the practising gastroenterologist.

Figure 1 |. Endoscopic findings in acute GVHD of the gastrointestinal tract.

Endoscopic images depict various endoscopic findings in acute graft-versus-host disease (GVHD) of the gastrointestinal tract. a | Colonic mucosa with a normal appearance following haematopoietic stem cell transplantation (HSCT) in a patient with diarrhoea. Non-targeted biopsies revealed mild acute GVHD. b | Sigmoid colonic mucosa with mucosal oedema, loss of normal haustra and complete loss of vascularity following HSCT in a patient with diarrhoea. Biopsies revealed mild acute GVHD. c | Colonic mucosa with oedema, exudates, deep ulcers (black arrow) and areas of necrotic tissue (white arrow) in a patient following HSCT with biopsies confirming severe acute GVHD. d | Colonic mucosa with oedema, friability, loss of vascularity and white plaques (arrow) in a patient following HSCT. Biopsies revealed moderate acute GVHD and pneumatosis intestinalis. e | Upper endoscopy in a patient with nausea and epigastric pain following HSCT, showing patchy, raised erythematous lesions (arrow) as well as localized superficial mucosal erosions. Biopsies of the lesions revealed mild acute GVHD. f | Duodenal mucosa in a patient with severe epigastric pain following HSCT, revealing loss of normal plicae circulares, the presence of friable and oedematous mucosa and a complete loss of normal vascularity. Biopsies revealed severe acute GVHD.

Figure 2 |. Recommended diagnostic algorithm for patients with suspected gastrointestinal acute GVHD after HSCT.

Post-haematopoietic stem cell transplantation (HSCT) patients who develop gastrointestinal symptoms must be carefully evaluated. The initial step is to review medications that might cause gastrointestinal adverse effects, assess for acute infection and rule out non-transplant-related gastrointestinal illness. If these aetiologies are excluded, graft-versus-host disease (GVHD) must be considered as a potential aetiology. If there is a high suspicion for gastrointestinal acute GVHD, empirical treatment can be initiated as the diagnostic work-up is undertaken. If there is a moderate or low suspicion for gastrointestinal acute GVHD, an endoscopic evaluation should be undertaken in accordance with the patient’s predominant symptoms (upper or lower gastrointestinal). Once a diagnosis is established, treatment should be promptly initiated. If the initial study is non-diagnostic but gastrointestinal acute GVHD is still a concern, further endoscopic evaluation should be undertaken. Once a diagnosis is established, appropriate therapy must be initiated. First-line therapy for GVHD typically includes corticosteroids.

Figure 3 |. Histopathological findings in GVHD of the gastrointestinal tract.

Haematoxylin and eosin (H&E) staining of acute graft-versus-host disease (GVHD) of the gastrointestinal tract, illustrating common histopathological findings. a | Oxyntic mucosa of the stomach showing apoptotic epithelial cells in multiple crypts (black arrows, ×200). The nuclei of the apoptotic cells shrink in size, the chromatin condenses and nuclear fragmentation occurs. b | Colonic mucosa depicting multiple withered and necrotic crypts (arrow heads, ×200). c | Colonic biopsy showing areas of extensive crypt loss (black arrow). The remaining two crypts (white arrows) show reactive epithelial changes (×100).

Figure 4 |. Gastrointestinal cytomegalovirus infection following HSCT.

Endoscopic and histopathological images from patients with acute graft-versus-host disease (GVHD) of the gastrointestinal tract, depicting cytomegalovirus infection in the post-haematopoietic stem cell transplantation (HSCT) setting. a | Colonoscopy in a patient following HSCT with established severe acute GVHD who is unresponsive to corticosteroids. Numerous raised white plaques (white arrows) are present throughout the colon. Biopsy samples of the lesions revealed extensive cytomegalovirus-infected cells and positive immunostaining for cytomegalovirus proteins. b | Colonoscopy in a patient following HSCT with severe acute GVHD and profuse haematochezia. Large, deep ulcers in the transverse colon (white arrows, which trace the rim of an ulcer), areas of active bleeding (asterisk) and diffusely oedematous colonic mucosa are seen. Biopsies of the mucosa revealed acute GVHD, whereas biopsies of the ulcer base stained positive for cytomegalovirus proteins by use of immunohistochemistry. c | Haematoxylin and eosin (H&E)-stained slide showing an area of a colon with crypt loss and multiple cytomegalovirus-infected endothelial cells (arrowheads, ×200). The cytomegalovirus-infected cells have large, smudgy, eccentric nuclei with prominent intranuclear and intracytoplasmic inclusions. d | Immunohistochemical staining of cytomegalovirus proteins (typically cytomegalovirus tegument component pp65) highlights cytomegalovirus-infected endothelial cells (dark brown immunostaining, ×200).