Graft Versus Host Disease: Causes, Symptoms, and Care

Graft versus host disease is an immune response that occurs after foreign tissue (graft) transplantation in the body. After transplantation, the immune cells of the graft recognize your body as a foreign body and attack it. It occurs within a hundred days after tissue transplant. It can damage your skin, gastrointestinal tract, lungs, and liver.

What is Graft Versus Host Disease?

Graft versus host disease (GVHD) is a systemic immune disorder in which donor T lymphocytes recognize the recipient’s tissues as foreign due to human leukocyte antigen (HLA) mismatches and initiate an immune-mediated attack. In this condition, the “graft” refers to the transplanted donor cells or tissue, while the “host” refers to the recipient’s body.

It is one of the most common complications after an allogeneic transplant (in which one person’s tissue is grafted to another person’s body). It is also more common in allogeneic stem cell transplantation and among older people.^[1]

Incidence of Graft Versus Host Disease

Acute graft versus host disease is a common complication of tissue transplantation. It is reported in about 20–80% of patients after allogeneic stem cell transplantation, depending on donor compatibility and prophylaxis protocols.^[2]

Types of Graft Versus Host Disease

There are two types of graft versus host disease:

Acute Graft Versus Host Disease:

It develops within the first 100 days after allogeneic transplantation. The primary organs affected are the skin, liver, and gastrointestinal tract, with hallmark symptoms including rash, diarrhea, abdominal pain, and jaundice.

Chronic Graft Versus Host Disease:

This type can occur anytime after tissue transplantation. It usually occurs within two years and affects the skin, gastrointestinal tract, liver, lungs, genitals, and joints. It often resembles autoimmune or fibrotic disorders and may persist long-term.^[3]

Causes of Graft Versus Host Disease

Graft versus host disease occurs after an allogenic transplant when donor immune cells recognize host HLA antigens as foreign. Normally, HLA markers protect cells from immune attack. In GVHD, even with partial compatibility, donor lymphocytes mount an immune response against the recipient’s tissues.

Figure 1(A)How skin graft-versus-host disease (GvHD) develops. In acute GvHD, tissue injury releases signals that trigger immune cells from the donor, leading to inflammation and skin damage. In chronic GvHD, ongoing immune activation, loss of immune balance, and abnormal repair processes cause long-term damage and skin scarring.(B1)Patient with severe acute skin GvHD (grade III).(B2)The same patient three weeks after treatment with mesenchymal stem cells. Images courtesy of Prof. Martin Bornhäuser (MK1, UKD TU Dresden). Established and Emerging Treatments of Skin GvHD. ResearchGate, 2022. Available at:ResearchGateunder License CC BY

People at a greater risk of graft Versus Host Disease:

You have a greater risk of this disease if:

• You receive an allogeneic stem cell or solid organ transplant (especially liver).
• Transfusion of mismatched blood
• You undergo chemotherapy or radiotherapy before transplantation, which increases tissue injury and immune activation.
• Unmatched donor cells (the donor and the body’s human leukocyte antigens (HLA) are different.

Signs & Symptoms

Acute Graft Versus Host Disease:

Symptoms involve:

Skin Changes:

The most common symptom of graft versus host disease is the appearance of rashes on the body that look like sunburns. These rashes can be itchy and painful. They are maculopapular and occur on the palms, soles, neck, and shoulders, and they can even spread all over the body. In addition to that, skin changes like eczema may occur.

(a,b) Extensive erythematous erosive plaques involving most of the back surface and upper limbs. (c,d) Extensive erythematous erosive plaques involving the lower limbs. Lesions measured approximately 5–10 cm in diameter. Image courtesy: Bullous Pemphigoid as a Manifestation of Graft-Versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Report of a Novel Case. ResearchGate 2025. Available at:ResearchGateUnder license CC BY 4.0

Gastrointestinal Symptoms:

Significant gastrointestinal symptoms are abdominal pain, diarrhea, nausea, and vomiting. In addition, it causes ulcer formation in the gastrointestinal tract.

Liver Involvement:

Liver damage from this disease causes jaundice (yellowness in the eyes and other skin) and abnormal liver function tests.

Chronic Graft Versus Host Disease:

Signs and symptoms of chronic graft versus host disease are:

• Skin rashes
• Nausea
• Dry mouth
• Vomiting
• Diarrhea
• Mouth ulcers
• Hair loss
• Jaundice (yellow discoloration of skin and eyes)
• Tiredness
• Dry cough
• Muscle cramps and pain
• Vision changes
• Dryness in the eyes

Grades & Stages of Graft Versus Host Disease

Doctors classify GVHD severity using the Glucksberg grading system and the International Bone Marrow Transplant Registry (IBMTR) index.

Skin:

• Stage 1:Maculopapular rash involves less than 25 percent of your body area
• Stage 2: Maculopapular rash over 25 to 50 percent of your body
• Stage 3: Generalized erythroderma
• Stage 4: Generalized erythroderma along with bullae on your skin

Liver:

• Stage 1: Bilirubin 2 to 3 mg/dL, and your aspartate transaminase levels are between 150 and 750
• Stage 2: Bilirubin levels from 3 to 6 mg/dL in your body
• Stage 3: Bilirubin levels from 6 to 15 mg/dL in your body
• Stage 4: Bilirubin levels >15 mg/dL

Gastrointestinal System:

• Stage 1: Diarrhea greater than 500 milliliters per day
• Stage 2: Diarrhea greater than 1000 milliliters per day
• Stage 3: Diarrhea greater than 1500 millilitres per day
• Stage 4: Diarrhea greater than 2000 millilitres per day or severe abdominal pain

Glucksberg Classification:

• Mild: Stage one or two of your skin involvement, no gastrointestinal system or liver involvement
• Moderate: Stage 1 to 3 of your skin involvement, along with stage 1 of your liver and gastrointestinal tract involvement
• Severe: Stage two to three of your skin involvement or gastrointestinal tract involvement
• Life-Threatening: Stage 1 to 4 of your skin involvement and stage 2 to 4 of your gastrointestinal tract involvement.^[4]

International Cone Marrow Transplant Registry Severity Index (IMBTR):

• Mild: No liver or gastrointestinal tract involvement, along with stage one of your skin involvement
• Moderate: Stage 2 of your skin involvement, along with Stage 1 or 2 liver and gastrointestinal tract involvement
• Severe: Stage 3 skin or gastrointestinal tract involvement
• Life-threatening: Stage 4 skin involvement or gastrointestinal tract involvement.^[5]

How to diagnose Graft Versus Host Disease?

The diagnosis requires a thorough history, examination, and relevant investigations.^[6]

History:

Your doctor may ask you questions about recent transplantation, timing of symptom onset, skin rashes, diarrhea, jaundice, or dryness of eyes/mouth.

Examination:

Your doctor performs a complete general physical examination. While examining your skin, they focus on any skin rashes, ulcerations, and jaundice. They also check for conjunctivitis, dry mouth, dry eyes, and oral ulcers.

Laboratory Tests:

The doctors may advise you to undergo laboratory tests like complete blood count (CBC), liver function tests (Alkaline phosphatase, serum bilirubin, alanine aminotransferase or ALT, aspartate aminotransferase or AST levels).

Biopsy:

As this disease affects the skin and gastrointestinal tract, the doctor may advise you to undergo a skin and gastrointestinal tract biopsy to assess their involvement.

Other Investigations:

Your doctor may go for investigations like X-ray abdomen, Computed tomography (CT) scan abdomen and chest, magnetic resonance imaging (MRI), andendoscopywhile diagnosing this disease.

Diagnostic criteria (Billingham):

1. The graft contains immunologically competent cells.
2. The host has alloantigens recognized as foreign.
3. The host cannot mount a sufficient immune response against the graft.

People who undergo hematopoietic stem cell transplantation have a greater risk of developing graft versus host disease.

Management of Graft Versus Host Disease

Management involves these steps:

Prophylactic Treatment:

Doctors give prophylactic immunosuppressive therapy to all patients undergoing tissue transplants to prevent graft versus host disease. A common regimen includes cyclosporine (or tacrolimus) combined with methotrexate, given for several months after transplantation. In addition, patients may receive antibiotics, antivirals, and antifungal drugs to reduce the risk of infection.

Glucocorticoids:

The next step in managing graft versus host disease is suppressing T lymphocytes, and corticosteroids remain the first-line treatment.

Grade 1

For grade one graft versus host disease, topical corticosteroids are usually the best treatment option. If symptoms do not improve, topical calcineurin inhibitors such as tacrolimus may be considered.

Grade 2 & Higher Grade

In grade two or higher graft versus host disease, systemic corticosteroids such as methylprednisolone (around 2 milligrams per kilogram per day) are recommended. If the gastrointestinal tract is involved, adding non-absorbable steroids like budesonide or beclomethasone may help. Steroids should be tapered gradually to prevent a rebound flare-up.

Chronic Graft Versus Host Disease

For chronic graft versus host disease, the use of steroids is continued for a longer duration. In some cases, long-term therapy is required. Adjunctive treatments, such as octreotide, may help control diarrhea associated with gastrointestinal involvement.

Calcineurin Inhibitors:

Doctors may advise you to use calcineurin inhibitors, such as cyclosporine, tacrolimus, and steroids, to manage this disease.

Anti-thymocyte Globulin:

Anti-thymocyte globulin is beneficial in severe or steroid-refractory graft versus host disease. It works by depleting T lymphocytes and suppressing the immune response.

Biological Therapies:

Doctors may also use monoclonal antibodies, TNF (tumor necrosis factor) inhibitors such as infliximab, or interleukin-targeted antibodies such as basiliximab, to suppress immune activity.

Photopheresis:

It helps manage chronic graft versus host disease. In this procedure, white blood cells are removed from the blood, treated with a photosensitizing agent, exposed to ultraviolet (UV) light, and then returned to the body.

Other Immunosuppressants:

Your doctors may advise you of other immunosuppressants like mycophenolate, etanercept, sirolimus, and alpha-1 antitrypsin while managing chronic graft versus host disease.

Supportive Care:

Correcting electrolyte imbalances, nutritional deficiencies, and maintaining overall organ support are necessary parts of comprehensive management.

Prognosis of GVHD

Graft versus host disease has a poor prognosis, with outcomes depending on severity and response to treatment. The five-year survival rate for grade C graft versus host disease is about 25 percent, while for grade 4, it drops to around 5 percent.^[7]

Extensive skin involvement, gastrointestinal symptoms, liver dysfunction, and thrombocytopenia are all associated with poorer outcomes.

Complications

This disease can lead to very severe complications involving multiple systems.

When it affects the respiratory system, it may cause pneumonia, bronchitis, bronchiectasis, bronchiolitis, and interstitial lung disease ( fibrosis ). Almost all of these diseases lead to symptoms of cough, shortness of breath, and fever.

The liver and biliary system involvement causes liver failure, jaundice, and cholangitis (inflammation of biliary ducts).

Complicated graft versus host disease may also involve gastrointestinal symptoms, producing symptoms of diarrhea, malabsorption, and dysphagia. Extreme organ involvement can also lead to organ failure.

Severe cases also affect other organs, such as the eyes, skin, and joints, and cause conjunctivitis, dry eyes, and joint inflammation. Some complicated cases also report skin cancer.

Treatment-related complications of graft versus disease lower the immunity of the patient due to immunosuppressant drugs and make him prone to recurrent infections.^[8]

Prevention

For the prevention, your doctors follow these strategies:

• Selection of human leukocyte antigens (HLA) compatible donors.
• Adequate use of immunosuppressant drugs like steroids, methotrexate, and mycophenolate before tissue transplantation.
• T lymphocyte depletion from donor grafts to reduce the risk of GVHD.

Moreover, early detection and management of symptoms reduces the risk of severe complications of graft versus host disease.^[9]

Conclusion

Graft versus host disease occurs after tissue is transplanted from another person into your body. It causes incompatibility of human leukocyte antigens (HLA), initiating an autoimmune response. Symptoms include skin rashes, ulcers, nausea, abdominal pain, hair loss, jaundice, and dryness in the mouth. Treatment of this disease involves immunosuppressants.

References

[1] Socié, G., & Ritz, J. (2014). Current issues in chronic graft-versus-host disease. Blood, 124(3), 374–384. https://doi.org/10.1182/blood-2014-01-514752

[2] MacMillan, M. L., Robin, M., Harris, A. C., DeFor, T. E., Martin, P. J., Alousi, A., Ho, V. T., Bolaños-Meade, J., Ferrara, J. L., Jones, R., Arora, M., Blazar, B. R., Holtan, S. G., Jacobsohn, D., Pasquini, M., Socie, G., Antin, J. H., Levine, J. E., & Weisdorf, D. J. (2015). A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality.Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation,21(4), 761–767.

[3] Lee, S. J., Vogelsang, G., & Flowers, M. E. (2003). Chronic graft-versus-host disease. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 9(4), 215–233.

[4] Glucksberg, H., Storb, R., Fefer, A., Buckner, C. D., Neiman, P. E., Clift, R. A., Lerner, K. G., & Thomas, E. D. (1974). Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation, 18(4), 295–304. https://doi.org/10.1097/00007890-197410000-00001

[5] Rowlings, P. A., Przepiorka, D., Klein, J. P., Gale, R. P., Passweg, J. R., Henslee-Downey, P. J., Cahn, J. Y., Calderwood, S., Gratwohl, A., Socié, G., Abecasis, M. M., Sobocinski, K. A., Zhang, M. J., & Horowitz, M. M. (1997). IBMTR Severity Index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. British journal of haematology, 97(4), 855–864.

[6] Tian, M., Lyu, Y., Wang, B., Liu, C., Yu, L., Shi, J. H., Liu, X. M., Zhang, X. G., Guo, K., Li, Y., & Hu, L. S. (2021). Diagnosis and treatment of acute graft-versus-host disease after liver transplantation: Report of six cases.World journal of clinical cases,9(30), 9255–9268. https://doi.org/10.12998/wjcc.v9.i30.9255

[7] Cahn, J. Y., Klein, J. P., Lee, S. J., Milpied, N., Blaise, D., Antin, J. H., Leblond, V., Ifrah, N., Jouet, J. P., Loberiza, F., Ringden, O., Barrett, A. J., Horowitz, M. M., Socié, G., Société Française de Greffe de Moëlle et Thérapie Cellulaire, Dana Farber Cancer Institute, & International Bone Marrow Transplant Registry (2005). Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: a joint Société Française de Greffe de Moëlle et Thérapie Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study. Blood, 106(4), 1495–1500.

[8] Pidala, J. A., Gooley, T. A., Luznik, L., & Blazar, B. R. (2024). Chronic graft-versus-host disease: unresolved complication or ancient history?.Blood,144(13), 1363–1373. https://doi.org/10.1182/blood.2023022735

[9] Choi, S. W., & Reddy, P. (2014). Current and emerging strategies for the prevention of graft-versus-host disease.Nature reviews. Clinical oncology,11(9), 536–547. https://doi.org/10.1038/nrclinonc.2014.102