Graft-versus-host disease (GvHD) is a systemic disorder that occurs when the graft's immune cells recognize the host as foreign and attack the recipient’s body cells. “Graft” refers to transplanted, or donated tissue, and “host” refers to the tissues of the recipient. It is a common complication after allogeneic hematopoietic stem cell transplant (HCT) .
GVHD has been classically classified based on the timing of presentation into acute and chronic using a cutoff of 100 days post-transplant. This has been further subclassified based on clinical manifestations accepted by the NIH into:
GvHD occurs in the following settings:
For GvHD to occur, immunologically competent cells should be transplanted into immunodeficient recipients and the transferred cells should recognize alloantigens in the host. Other important factors that determine the occurrence and severity of GvHD are:
Acute GVHD can occur in up to 50% of patients receiving hematopoietic stem cell transplantation (HCT) from a human leukocyte antigen (HLA)-matched sibling  . The occurrence is typically higher in unmatched donors. The incidence of chronic GVHD ranges from 6% to 80% . GVHD is considered one of the main causes of morbidity and mortality after HCT; more than 10% of patients will die from this complication .
Risk factors of acute GVHD are higher degrees of HLA mismatch, prior acute GVHD gender disparity, older age of the donor and/or recipient, peripheral stem cell recipients, alloimmunization of the donor, Cytomegalovirus and Epstein Barr virus seropositivity .
Cells of the immune system are trained early to differentiate between "self" cells and "non-self" cells. The ability to recognize "non-self" cells depends on a set of genes knows as the histocompatibility genes that provide instructions for making a group of related proteins known as major histocompatibility complex (MHC proteins) or human leukocyte antigens (HLA). The histocompatibility genes code for MHC class I proteins that are present on all nucleated cells in the body and MHC class II molecules that are expressed only on antigen-presenting cells. During transplantation, the donor tissue is usually obtained from a genetically different individual known as an "allograft". Immune cells in the graft recognize the MHC proteins of the recipient tissue as "non-self" and triggers an immune response between the donor and the recipient.
Donor cytotoxic CD-8 t cells recognize host tissue as foreign and proliferate to cause severe organ damage (type IV cytotoxic T cell hypersensitivity reaction). Donor allograft T-cells are the main effector cells for GvHD and its pathogenesis can be divided into three phases (Figure 1) .
In the gastrointestinal tract, apoptosis of epithelial cells is the most important feature. Dilated crypts, crypt destruction, villus atrophy, neutrophilic infiltration can also be seen in small bowel specimens . Liver biopsy shows dysmorphic small bile ducts with portal inflammation. Histopathological damage of the skin ranges from minimal vacuolization to separation of the dermis from the epidermis. Grades of skin graft-versus-host-disease are as follows (Figure 2): 
Acute GVHD usually involves the skin, gastrointestinal tract, and liver, and is seen in 70%, 74%, and 44%, respectively. It can also involve the lungs, kidneys, eyes, and hematopoietic system. It may also result in decreased responsiveness to active immunization.
The most common skin manifestation is a pruritic or painful maculopapular rash that initially involves the palms, soles shoulders, and nape of the neck. It can spread diffusely and become confluent. In severe GVHD, bullous lesions with toxic epidermal necrolysis mimicking TEN can develop.
GI symptoms most commonly include diarrhea and abdominal pain, but mucositis, mucosal ulceration, nausea, and vomiting can also occur. Diarrhea is secretory and continues despite fasting. Diarrhea initially is watery, but may progress to become bloody, and may require frequent blood transfusions and cause difficulty in maintaining adequate fluid balance.
Liver involvement usually presents together with either cutaneous or GI manifestation, it rarely occurs in isolation. Abnormal liver function tests are characteristic, typically with elevated bilirubin and alkaline phosphatase levels. Coagulopathy and hyperammonemia are rare but can occur in severe forms. Hepatomegaly, as well as, pale urine and stool may be present.
Chronic GVHD has many features in common with collagen vascular disorders and systemic sclerosis . In the oral cavity, chronic GVHD may present as lichen planus with a risk of development to oral squamous cell carcinoma that differs from the classical pathology and seems to be more aggressive in patients with stem cell transplantation . Recurrent infections can be a cause of death, and it is often a complication of immunosuppression . Ocular involvement is an indicator of poor prognosis in GVHD. It usually affects the ocular surface and manifests with dry eye or keratoconjunctivitis sicca .
Diagnosis is usually clinical. Traditionally the criteria as described by Billingham include the following: 
Immunologically competent cells must be present in the graft.
The recipient should have transplantation alloantigens that appear foreign to the graft and can therefore stimulate it antigenically.
The recipient should not be capable of mounting an effective immunologic reaction against the graft, or it must allow for enough time for the graft to manifest an immune response.
All patients who underwent hematopoietic cell transplantation are at potential risk of GVHD, although it usually occurs during the first few months post-transplantation . Skin and gastrointestinal (usually rectal) biopsies can help confirm the diagnosis. The staging of the disease is based on the extent of symptoms and lab abnormalities.
The use of biomarkers for the diagnosis and prognosis estimation is an area of investigation. Currently, no biomarker is ready for clinical application, but examples include ST2, REG3alpha, and TNFR1   .
All patients receiving HCT should undergo prophylactic treatment for GVHD. Treatment protocols differ by institution, but most commonly use a combination of cyclosporine and methotrexate is continued for several months post-transplantation. Antibacterial, antiviral, and antifungal prophylaxis is typically added post HCT to mitigate the risk of infections.
Treatment for GVHD depends on the severity of symptoms and organs involved. Most treatment options focus on immunosuppression of donor T cells and must be balanced to reduce the symptoms of GVHD while avoiding decreasing the beneficial graft vs. tumor (GVT) response. Corticosteroids remain the most commonly used treatment.
Grade 1 GVHD is usually managed with topical steroids in an attempt to control local symptoms. Topical tacrolimus is an option for steroid-resistant disease.
Grade 2 or higher requires the addition of systemic steroids, most commonly methylprednisolone 2 mg/kg/day in divided doses. In cases of GI involvement, the addition of a nonabsorbable corticosteroid (budesonide or beclomethasone) is more effective than systemic treatment alone. Steroids should be avoided if a GI infection is present.
Gradual tapering of the steroid over the course of several months is important to prevent a GVHD flare. Patients with chronic GVHD will typically require prolonged courses of steroids, generally 2 - 3 years. Some patients may require lifelong treatment. Octreotide can be added in an attempt to decrease the amount of diarrhea.
The addition of other agents to steroids include mycophenolate, etanercept, pentostatin, monoclonal antibodies, sirolimus, alpha-1-antitrypsin, mesenchymal stromal cells, and extracorporeal photopheresis. However, their efficacy is unclear.
Cyclosporine can be added to the treatment regimen for chronic GVHD in an attempt to decrease steroid dosage and duration.
The differential diagnosis depends on the clinical manifestations:
Drug reactions, viral exanthems, radiation dermatitis
Infection, especially viral hepatitis, drug-induced liver injury, shock liver, immunotherapy-related hepatotoxicity, sinusoidal obstructive syndrome, and malignancy .
Diarrhea: iatrogenic (secondary to chemotherapy, immunosuppressants, antibiotics or magnesium), infectious (CMV, EBV, Adenovirus, Rotavirus, Clostridium difficile, Mycobacterium avium complex, Giardia, Cryptosporidium), thrombotic microangiopathy, bile-salt malabsorption
Nausea and vomiting, anorexia: iatrogenic (secondary to chemotherapy, immunosuppressants, radiation, antibiotics, opioids) .
The two most famous systems for acute GVHD staging are the International Cone Marrow Transplant Registry (IBMTR) system (A-D) and Glucksberg grade (1-4) . Staging is based on clinical manifestations and severity of organ involvement .
Glucksberg grade :
International Cone Marrow Transplant Registry (IBMTR) Severity index :
Mortality is generally higher in moderate to severe GVHD in comparison with mild disease  . The 5-year survival rate of grade C is 25%, while grade 4 has a survival rate of 5% . There is a strong correlation between the response to first-line treatment and survival .
GVHD is a complication of allogeneic hematopoietic stem cell transplant that can usually have other complications, including bronchiolitis obliterans syndrome, interstitial lung disease, obliterative bronchiolitis, organizing pneumonia, and pleuroparenchymal fibroelastosis.
Reported complications include gastrointestinal involvement resulting in fibrosis, motility abnormalities, and malabsorption. Lung problems may cause bronchiectasis. Infection is common and fatal.
Liver complications include endothelialitis, bile duct destruction, and pericholangitis, but a liver biopsy is not done routinely due to associated thrombocytopenia.
Nutritionists should evaluate patients with GI involvement due to a higher risk of malnutrition and abnormalities in zinc, magnesium, vitamin B12, and vitamin D .
Along with the timely appropriate treatment and prophylactic measures, patients can receive counseling and education about some remedial measures to improve the management of GVHD.
Skincare: Usage a moisturizer, application of sunscreen lotion with appropriate SPF when going out to the sun, avoid scratching on the sutured area, or other regions, wearing long sleeves and pants.
Mouth care: dental hygiene with topical fluorides is suggested .
Diet: Utmost care on choosing what to eat. Better to avoid substances that can cause loose stools such as spicy food.
Hygiene: Staying away from infective sources, wearing a face and nose mask when going out, keeping the hands and feet clean.
All the patients and caregivers should take vaccines against influenza and pneumococcus .
An interprofessional team should educate the parents and manage patients with a likelihood of developing GVHD. Primary care providers should refer patients known to have T-cell immunodeficiency to a hematologist to prevent infections and other complications. Coordination of care must occur between the transplant team and the patient's primary provider to optimize treatment and avoid complications. Transplant nurses monitor patients, report issues, and provide patient and family education. [Level 5]
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