Graft-versus-host disease (GVHD) refers to multiorgan dysfunction resulting from the introduction of foreign immunocompetent lymphocytes or bone marrow tissue (the graft) into an immunologically defective host. Most GVHD occurs in patients who have undergone allogeneic bone marrow transplants, but it may occur in solid organ transplant and blood transfusion recipients. Rarely, a GVHD-like syndrome can occur following autologous hematopoietic stem cell transplantation, likely due to failure to re-establish self-tolerance. The skin, the gastrointestinal (GI) tract, and the liver are the main organs involved in acute GVHD.

Cutaneous GVHD has both an acute and a chronic form. Acute disease normally occurs within 2-4 weeks of stem cell infusion around the time of engraftment, and it typically presents as a morbilliform eruption that may progress to erythroderma or, rarely, a toxic epidermal necrolysis-like illness. Inflammation is triggered by sterile damage-associated molecular pattern (DAMP) and pathogen-associated molecular pattern (PAMP) molecules. Chronic cutaneous GVHD usually presents with mucocutaneous manifestations a mean of 4 months after transplantation; sclerotic and nonsclerotic (lichen planus-like) skin lesions are most common.

Pathophysiology of acute GVHD derives from activation of host antigen-presenting cells (APCs) secondary to diffuse tissue damage caused by the underlying disease and by the pretransplantation conditioning regimen. Additionally, tissue injury to the GI tract increases the systemic inflammasome by translocation of PAMP molecules. Activated APCs then induce donor T-lymphocyte priming and proliferation, which triggers a CD8+ / natural killer (NK) effector response, with local tissular amplification by soluble inflammatory cytokines such as γ-IFN and TNF-α.

Clinical staging of acute cutaneous GVHD:

• Stage 1 – < 25% body surface area involved
• Stage 2 – 25%-50% body surface area involved
• Stage 3 – > 50% body surface area involved or generalized erythroderma
• Stage 4 – generalized erythroderma with blister formation and desquamation

Clinical staging of acute hepatic GVHD:

• Stage 1 – bilirubin 2-3 mg/dL
• Stage 2 – bilirubin 3-6 mg/dL
• Stage 3 – bilirubin 6-15 mg/dL
• Stage 4 – bilirubin >15 mg/dL

Clinical staging of acute GI GVHD:

• Stage 1 – nausea / vomiting or diarrhea 500-1000 mL/day
• Stage 2 – diarrhea 1000-1500 mL/day
• Stage 3 – diarrhea > 1500 mL/day
• Stage 4 – severe abdominal pain ± noninfectious paralytic ileus or hematochezia

Classification of acute GVHD:

• Hyperacute – onset prior to day 14 following transplant
• Classic acute – onset prior to day 100 following transplant
• Persistent, recurrent, late-onset acute – onset after day 100 following transplant or donor lymphocyte infusion

Acute GVHD occurs with mild-to-moderate severity (stage 1-2) in about 30%-40% of patients who have received allogeneic bone marrow transplants. Organs involved most frequently with GVHD are the skin, liver, and intestinal mucosa; limited skin involvement is most common. The incidence and severity of the disease correspond with the degree of major histocompatibility antigen (MHC) mismatch between the donor and the host, but other key factors related to the development of acute GVHD include increased age of transplant recipient and sex mismatch between donor and recipient as well as the GVHD prophylaxis given to the stem cell recipient.

Hyperacute GVHD occurring within 14 days after transplantation accounts for about 27% of all cases of acute GVHD, and it involves the skin in about 88% of patients. Hyperacute GVHD manifests with high fevers and with more severe skin disease, lower response to topical steroids, and higher nonrelapse mortality compared to regular acute GVHD. Risk factors for hyperacute GVHD include mismatched related or matched unrelated donor, donor-recipient sex mismatch, a myeloablative conditioning regimen, and receipt of over 5 prior chemotherapy regimens.

GVHD is the major cause of nonrelapse morbidity and mortality among stem cell transplant recipients.