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

Cutaneous GVHD has both an acute and a chronic form. The skin, the gastrointestinal (GI) tract, and the liver are the main organs involved in acute GVHD.

Classification of acute GVHD:

• Hyperacute – Onset occurs prior to day 14 following transplant. It 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.
• Classic acute GVHD – Starts less than 100 days after transplant (typically within 2-4 weeks of stem cell transplant). Skin involvement typically presents as a morbilliform eruption that may progress to erythroderma or, rarely, a toxic epidermal necrolysis-like illness; 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.
• Late-onset acute GVHD – Presents after 100 days.

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 pathogen-associated molecular pattern (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.

There are 2 common grading criteria for acute GVHD, including the modified Glucksberg-Seattle criteria and the International Bone Marrow Transplant Registry (IBMTR) Severity Index. 

Modified Glucksberg-Seattle Criteria:

• Grade I:
• Skin: rash covering < 25% of body surface area (BSA)
• Liver: bilirubin 2-3 mg/dL
• GI: diarrhea < 500 mL/day or persistent nausea
• Grade II:
• Skin: rash covering 25%-50% of BSA
• Liver: bilirubin 3.1-6 mg/dL
• GI: diarrhea 500-1000 mL/day
• Grade III:
• Skin: rash covering > 50% of BSA
• Liver: bilirubin 6.1-15 mg/dL
• GI: diarrhea 1000-1500 mL/day
• Grade IV:
• Skin: generalized erythroderma with bullae
• Liver: bilirubin > 15 mg/dL
• GI: diarrhea > 1500 mL/day or severe abdominal pain with or without ileus

IBMTR Severity Index:

• Index A: Mild skin involvement without significant liver or GI involvement
• Index B: Moderate skin involvement or mild liver / GI involvement
• Index C: Severe skin involvement or moderate liver / GI involvement
• Index D: Severe liver / GI involvement or multiorgan severe involvement

Chronic GVHD:

• Classic – Without preceding acute GVHD, develops more than 100 days after transplant (mean onset of 4 months). Sclerotic and nonsclerotic (lichenoid) skin lesions are most common.
• Overlap – Features of both acute and chronic GVHD occurring more than 100 days after transplant.