Graft-versus-host disease overview

# Overview
Graft-versus-host disease (GvHD) is a common complication of allogeneic bone marrow transplantation in which functional immune cells in the transplanted marrow recognize the recipient as "foreign" and mount an immunologic attack. It is a pathologic condition characterized by recipient tissue damage that arise from immunological activation of donor T lymphocytes. Donor T cells typically mount a response against foreign host cells in the gastrointestinal system, liver, and skin. It occurs in 40-60% of patients undergoing stem cell transplant. Acute GvHD typically occurs within 100 days of transplant. Chronic GvHD occurs after 100 days from transplant.  Nearly 40% of patients will develop some form of GvHD, whether it is acute or chronic.

# Historical Perspective
The first observation of GvHD was noted in the 1920s when researchers studied chicken embryos and noted immunological activation in the presence of foreign material. Given the immunologic pathogenesis of the disease, corticosteroids were used, and it was noted that steroids could induce an excellent response.

# Classification
The classification of GvHD is based on both severity and time of onset. The severity is based upon the stage and grade. The conglomeration of stages of GvHD of each organ affected gives rise to the overall grade. Each affected organ has a staging system (stages 1-4), depending on the degree of organ dysfunction. The time of onset determines whether GvHD is acute or chronic. Acute GvHD occurs within the first 100 days of stem cell transplant. Chronic GvHD occurs after 100 days from transplant.

# Pathophysiology
The pathophysiology of GvHD involves immune activation of donor-derived T cells, which mount a response against host tissue, especially the liver, skin, and GI tract. Antigen-presenting cells (APCs) are key players in the initiation of the process. Immune activation leads to inflammation and organ destruction. Acute and chronic GvHD have slightly different pathophysiologic mechanisms.

# Causes
The cause of GvHD is stem cell transplantation from an allogeneic donor, typically a donor that has few human leukocyte antigen (HLA) similiarities compared to the recipient.

# Differentiating GvHD from Other Diseases
Other possible etiologies for liver dysfunction in a patient who received stem cell transplant include CMV hepatitis and veno-occlusive disease. It is important to differentiate these etiologies from GvHD, as the treatment implications are different.

# Epidemiology and Demographics
GvHD can occur in any population. Certain subsets of donor cells are less likely to result in GvHD, such as umbilical cord blood-derived stem cells, which contain fewer T cells than other sources of stem cells. There are no known racial disparities for GvHD. There are no particular geographic areas that are more prone to GvHD.

# Risk Factors
One major risk factor for GvHD is HLA-mismatched donor source. The greater the degree of mismatch, the greater the likelihood for GvHD. Another common risk factor is the use of total body irradiation as the conditioning regimen.

# Screening
There is no role for screening (secondary prevention) for GvHD. However, there is a significant role for primary prevention in GvHD. Such primary prevention measures include medications like methotrexate and antibiotics like ciprofloxacin for gut decontamination.

# Natural History, Complications, and Prognosis

## Natural History
The natural history of GvHD is variable from patient to patient. For mild forms of GvHD, the disease is expected to abate after immunosuppressive therapy is started. In severe cases of GvHD, the natural history is such that immune activation continues for quite some time, and the disease can be refractory to therapy. For steroid-refractory GvHD, the morbidity and mortality is very high, and the natural history of the disease terminates with organ failure and death.

## Complications
The complications of GvHD stem from the resultant end-organ damage that occurs from immune activation. Complications include debilitating GI symptoms (including life-threatening diarrhea and abdominal pain), disruption of the GI mucosa and subsequent bacterial translocation and sepsis, liver failure, and skin infections.

## Prognosis
The prognosis of GvHD is variable based on the severity of disease. Steroid-refractory GvHD has a much poorer prognosis then steroid-responsive GvHD.

# Diagnosis

## Diagnostic Criteria
The diagnosis of GvHD can be based via tissue biopsy of the suspected organ involved. For GI GvHD, endoscopy or colonoscopy with mucosal biopsies can be done to confirm the diagnosis. For liver GvHD, a liver biopsy can confirm the diagnosis. For skin GvHD, punch biopsies of the skin can confirm the diagnosis. Typical histologic findings include vacuolar interface dermatitis.

## History and Symptoms
The symptoms are based on the organs involved. Skin symptoms include maculopapular rash and erythema. Liver symptoms include jaundice, pruritis, edema, and abdominal pain. GI symptoms include diarrhea, abdominal pain, and bleeding.

## Physical Examination
The physical exam of a patient with GvHD should focus on the organs involved. Skin exam findings include erythema and rash. Liver exam findings include tender hepatomegaly, edema, and jaundice. GI exam findings include abdominal tenderness.

## Laboratory Findings
For liver GvHD, abnormal liver function testing can be seen. This includes elevated alanine aminotransferase, elevated aspartate aminotransferase, hyperbilirubinemia, elevated alkaline phosphatase, elevated prothrombin time, and elevated partial thromboplastin time.

## Imaging Findings
There is no specific role for imaging in GvHD. Chest X-ray can show evidence of pneumonitis if there is immunological attack in the lungs. CT of the abdomen can show inflammation in the intestines if there is evidence of GI GvHD.

## Other Diagnostic Studies
Endoscopy and colonoscopy can be used to assess for inflammation the GI mucosa and can be used to help biopsy mucosa to determine a pathologic diagnosis for GI GvHD. Liver biopsy can be done to assess for a pathologic diagnosis of liver GvHD. Skin biopsy can be done to assess for a pathologic diagnosis of skin GvHD.

# Treatment

## Medical Therapy
Medical therapy focuses on immunosuppressive medications, since GvHD is an abnormal and intense immunological phenomenon. Steroids are the first line of therapy. Other treatment options include alternative immunosuppressive medications like tacrolimus or mycophenolate.

## Surgery
There is no role for surgery in the management of GvHD. However, if GvHD becomes very severe to the point of organ dysfunction requiring surgery, surgery may be indicated in the correct clinical context.

## Prevention
Prevention of GvHD is based on primary preventive strategies, including use of donor stem cells that are closely HLA-matched to the recepient, the use of methotrexate in the first 11 days immediately post-transplant, and the use of anti-microbial agents to prevent GI inflammation and infection. There is no role for secondary prevention.