Symptoms of acute graft-versus-host-disease are primarily the result of damage to the liver, skin and the gastrointestinal tract. The disorder may also target the hematopoietic system, bone marrow, and the lungs. Chronic graft-versus-host-disease can also cause damage to the connective tissue. Acute graft-versus-host-disease usually presents within three to four weeks of transplantation with a painful, pruritic rash [5]. In the most severe cases symptoms may include fever, erythroderma, and peeling of the skin. Liver involvement in graft versus host disease is measured by the bilirubin level.

Further symptoms of graft-versus-host-disease include:

• Red rash, appearing first on the palms of the hands, soles of the feet, face, and upper trunk
• Conjunctivitis
• Jaundice due to liver involvement, rarely hepatic coma
• Diarrhea, gastric bleeding, nausea, and vomiting
• Abdominal pain and ileus
• Lichenoid thickening of the skin which may cause contractures
• Dryness of mouth, gastritis, anorexia and dyspepsia
• Bronchiolitis
• Increased risk of infection
• Thrombocytopenia and anemia
• Ocular irritation, photophobia
• Obstructive pulmonary disease
• Weakness, neuropathic pain

• Weight Loss

  Digestive tract (gut): Symptoms include poor appetite, nausea, difficulty swallowing, vomiting, and weight loss. Lungs: Symptoms include shortness of breath, wheezing, pneumonia, or chronic bronchitis. [bmt.umn.edu]

  It may also cause hair loss, weight loss, vaginal dryness, cough, shortness of breath and joint problems. [leukemiabmtprogram.org]

  Symptoms of chronic disease include hair loss, skin rash, Sjögren syndrome (or sicca syndrome), hepatitis, and weight loss. [britannica.com]

• Fever

  Two weeks after surgery she presented with complaints of fever, nausea, vomiting, upper abdominal discomfort, diarrhea, skin rash and petechie all over the body. [ncbi.nlm.nih.gov]

  Symptoms to report Because of the increased risk of developing infections, it is very important to report any fevers of 100.4° F or higher to your BMT Coordinator during business hours. [my.clevelandclinic.org]

• Anemia

  No, GvHD is not a good thing for diseases such as Aplastic Anemia. [marrowmatters.com]

  Severe anemia may also result from gastrointestinal bleeding. Graft-versus-host-disease may cause permanent damage to affected tissues, liver, skin, mucous membranes of intestinal tract, and lungs. This damage is a result of inflammation. [symptoma.com]

  […] treatment in patients with cGVHD include fatigue, bruising, diarrhea, low levels of blood platelets (thrombocytopenia), muscle spasms, swelling and sores in the mouth (stomatitis), nausea, severe bleeding (hemorrhage), low levels of red blood cells (anemia [pharmacytimes.com]

  The most common adverse reactions (≥20%) were fatigue, bruising, diarrhea, thrombocytopenia, stomatitis, muscle spasms, nausea, hemorrhage, anemia, and pneumonia. Atrial fibrillation occurred in one patient (Grade 3). [fda.gov]

  Relation to bone marrow failure diseases: GVHD can result from having a stem cell transplant (also called a bone marrow or peripheral blood or umbilical cord transplant) to cure the aplastic anemia, MDS, or PNH. [aamds.org]

• Tachypnea

  General examination revealed tachypnea (respiratory rate: 18/min, SpO2: 97% at room air), tachycardia (pulse 96/min), fever (100°F), normal blood pressure (120/78 mmHg), oral mucosal erythema with extensive oropharyngeal candidiasis, ankle edema, icterus [ncbi.nlm.nih.gov]

• Diarrhea

  In the presence of a highly immunocompromised state, diarrhea and rashes, a diagnosis of GVHD needs to be considered. Kidney function impairment may be involved. [ncbi.nlm.nih.gov]

• Nausea

  Liver: jaundice (the skin and/or whites of your eyes turn yellow) itchy skin nausea and/or vomiting mild tenderness in the upper right stomach Patients who have acute GVHD are more likely to develop the chronic form later on. [myhealth.alberta.ca]

  GVHD of the stomach causes nausea, poor appetite, and vomiting. To diagnose gut GVHD, the transplant team will recommend a biopsy of your child's upper and/or lower digestive tract. [bmt.umn.edu]

  Acute GVHD can also cause: stomach and intestinal pain vomiting cramping nausea watery or bloody diarrhea elevated liver enzymes Reducing the Risk of Acute GVHD. [bmtinfonet.org]

  You may also have nausea, vomiting, or diarrhea. Some of these symptoms can be side effects of the transplant or of procedures or medications that go along with it. They can also mean you have an infection. [webmd.com]

• Vomiting

  Liver: jaundice (the skin and/or whites of your eyes turn yellow) itchy skin nausea and/or vomiting mild tenderness in the upper right stomach Patients who have acute GVHD are more likely to develop the chronic form later on. [myhealth.alberta.ca]

  GVHD of the stomach causes nausea, poor appetite, and vomiting. To diagnose gut GVHD, the transplant team will recommend a biopsy of your child's upper and/or lower digestive tract. [bmt.umn.edu]

  Mycophenolate is associated with GI disturbances, particularly diarrhoea and vomiting. [pharmaceutical-journal.com]

  […] symptoms Symptoms of acute GVHD include: burning and redness of the skin on the palms of the hands or soles of the feet rashes that can spread over the entire body blisters and peeling skin diarrhea, loss of appetite, cramping or abdominal pain, nausea and vomiting [cancer.ca]

• Abdominal Pain

  We report the case of a 37-year-old man with a previous bone marrow transplantation presenting with abdominal pain, diarrhoea and jaundice. [ncbi.nlm.nih.gov]

  Graft-versus-host disease USMLE® Step 1 style questions 1 questions Preview A 46-year-old woman comes to the emergency department because of fever, abdominal pain, and a rash for the past 6 hours. [osmosis.org]

  Clinical description Three organs are involved: the skin (rash/dermatitis), liver (hepatitis/jaundice), and gastrointestinal tract (abdominal pain/diarrhea). Either one or more of these organs may be affected. [orpha.net]

• Loss of Appetite

  Symptoms of chronic GVHD include: skin problems such as dryness, rash, itching, peeling, darkening, hard texture and feeling tight dry eyes that may have a burning or gritty feeling a dry mouth with or without mouth ulcers diarrhea, loss of appetite, [cancer.ca]

  Patients with GVHD may experience Loss of appetite Unexplained weight loss Nausea Vomiting Diarrhea Stomach pain Lungs. [lls.org]

  Both types often affect the: Eyes, causing conjunctivitis, dryness and irritation, itching Skin, causing rash and itching Liver, causing jaundice and/or hepatitis Stomach and intestinal tract, resulting in loss of appetite, cramping pain, diarrhea and [ucsfbenioffchildrens.org]

  […] of appetite Nausea, vomiting or diarrhea At its worst, GVHD can be debilitating, affecting quality of life. [medstargeorgetown.org]

• Dental Caries

  Patients with dry mouth may have difficulty chewing and swallowing foods, may notice changes in taste, and are at increased risk for developing dental caries, especially along the gum line and interproximally, between the teeth (Panel D). [aaom.com]

• Skin Rash

  Stages of Acute GVHD Stage 1 (mild) A skin rash over less than 25% of the body Stage 2 (moderate) A skin rash over more than 25% of the body, plus Mild liver or stomach and intestinal problems Stage 3 (severe) Redness of the skin, similar to a severe [nationwidechildrens.org]

  The reason to pursue a tissue biopsy is to help differentiate from other diagnoses which may mimic GVHD, such as a viral infection (hepatitis, colitis) or drug reaction (causing skin rash). [orpha.net]

  It must be suspected in patients with elevated liver enzymes and cholestasis, especially in those with a history of preceding skin rash and diarrhea. [ncbi.nlm.nih.gov]

  People may experience pain or itching with these skin rashes. This rash can spread to the trunk of the body. [medicalnewstoday.com]

• Blister

  Symptoms include jaundice, skin rash or blisters, a dry mouth, or dry eyes. Also called GVHD. [cancer.gov]

  […] skin rash over a more than 25% of the body accompanied by mild liver or stomach and intestinal disorders Stage 3 (severe) redness of the skin, similar to a severe sunburn, and moderate liver, stomach and intestinal problems Stage 4 (life-threatening) blistering [kiadis.com]

  Severe problems with acute GVHD may include blisters on the skin, watery or bloody diarrhea with cramping, and jaundice (yellowing of the skin and eyes) reflecting liver involvement. [medicinenet.com]

• Alopecia

  […] irritation and redness Skin thickening, scaling, hyper- or hypopigmentation (resembling lichen planus) Loss of skin colour without thickening ( vitiligo ) Hardening of skin ( scleroderma ) may interfere with joint mobility Hair loss (including typical alopecia [dermnetnz.org]

  Examination showed diffuse spotted hyper and hypopigmented skin, multiple lichenoid and atrophic lesions plus almost complete scarring alopecia, acral edema and erythema plus onychodistrophia of the 20 nails ( Figures 1 - 4 ). [scielo.br]

  Chronic disease can produce a similar skin rash, a tightening or an inflammation of the skin, lesions in the mouth, drying of the eyes and mouth, hair loss ( alopecia ), liver damage, lung damage, and indigestion. [encyclopedia.com]

• Eczema

  External stimuli, most notably, bacterial antigens, will influence the severity of eczematoid GVHD, as with other forms of eczema. [jamanetwork.com]

  Skin changes sometimes attributed to chronic GVHD include eczema and ichthyosis. Hypothyroidism may also cause skin changes and hair loss. Adrenal insufficiency in patients after steroid use may cause fatigue and nausea. [cancertherapyadvisor.com]

  Archer E, Chuang TY, Hong R (1990) Severe eczema in a patient with DiGeorge’s syndrome. Cutis 45:455–459 PubMed Google Scholar 36. [doi.org]

• Pruritic Rash

  Acute graft-versus-host-disease usually presents within three to four weeks of transplantation with a painful, pruritic rash. In the most severe cases symptoms may include fever, erythroderma, and peeling of the skin. [symptoma.com]

• Dysarthria

  A 59-year-old woman presented with right upper extremity weakness and dysarthria 33 months after undergoing matching allogenic bone marrow transplantation. [ncbi.nlm.nih.gov]

There is no validated diagnostic blood test for acute graft-versus-host-disease. Workup of patients suspected of having acute graft-versus-host-disease should begin with a complete history and physical. The history of recent transplantation or transfusion is essential for diagnosis. The time of symptom appearance will designate acute from chronic disease. Physical examination will show distinctive rash, red raised rash primarily of face, palms, soles, and upper trunk. Jaundice may be present with liver involvement. Lesions, inflammatory or lichen-like, may occur on the oral mucosa. Conjunctivitis will also be apparent.

Workup should also include the following studies:

Laboratory studies

• Complete blood count (CBC) may show thrombocytopenia, anemia, or leukopenia
• Liver function tests with elevated alkaline phosphatase, hypoalbuminemia
• Serum electrolytes, potassium, magnesium, bicarbonate levels may be altered

Other tests

• Schirmer test measures tear production by the lacrimal glands
• Pulmonary function tests
• Arterial blood gases
• Biopsy

Imaging

• Hepatic sonogram
• Upper GI endoscopy and barium swallow
• Sigmoidoscopy or colonoscopy

• Anergy

  Blockade of LIGHT/LTβ and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease. J. Clin. Invest. 109, 549–557 (2002). 141. Hubbard, V. M. et al. [doi.org]

• Liver Function Tests Abnormal

  Blood analyses were negative for the following tests: electrolyte abnormalities, liver function tests abnormalities, anti-neuronal antibodies, and vitamin B1, B3, and B6 deficiencies. Thyroid tests were normal. [bloodadvances.org]

  A new elevation in liver function tests or abnormal pulmonary functions tests needs to be investigated, not simply attributed to GVHD. When do you need to get more aggressive tests? Biopsy is indicated whenever there is a question of the diagnosis. [cancertherapyadvisor.com]

• Hemoglobin Decreased

  * Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased). [news.abbvie.com]

The primary intervention for acute graft-versus-host-disease is prevention. A 6 month course of cyclosporin A or tacrolimus, together with a short-course of methotrexate, should precede or follow transplantation. Antithymocyte globulin (ATG) may also be given prophylactically [6]. Better typing and correlation of donor and host to prevent dissimilarities may do much to preventing the disease. Treatment with high-dose systemic steroids is still the primary therapy of graft versus host disease after more than 25 years. However, the complete response rate is only about 35%.

Acute graft-versus-host-disease

Primary

• Corticosteroid immunosuppressive drugs, prednisone.
• The addition of methylprednisolone (1-60 mg/kg /day)
• For skin topical corticosteroids may be used
• Other therapies: Antithymocyte globulin (ATG), cyclosporine, or mycophenolate mofetil

Secondary

• Antithymocyte globulin or methylprednisolone at doses higher than initially
• Muromomab
• Ultraviolet A irradiation (PUVA) for cutaneous lesions

Chronic graft-versus-host-disease

• Prednisone, 1 mg/kg every other day
• Cyclosporine, 6 mg every 12 hours every other day
• Thalidomide

If chronic graft versus host disease persists:

• Azathioprine, alternating with cyclosporine and prednisone
• Clofazimine for skin and oral lesions
• Ultra-violet treatment or photopheresis for lesions that do not respond
• Rituximab for musculoskeletal symptoms

In efforts to improve the survival rate, the addition of antithymocyte globulin, CD5-immunotoxins, or interleukin-2 antagonists have not been effective. Further research and the development of new therapies are needed. The use an anti-TNFα agents, infliximab or etanercept, are being studied to treat steroid-refractory graft versus host disease [7].

If the graft-versus-host-disease is severe, stage 4, or requires intense immunosuppression, the patient is susceptible to severe infections that may result in death. Increased susceptibility to infection, particularly Streptococcus pneumonia and Haemophilus influenzae pneumonia, occurs in 50% of patients with acute graft-versus-host-disease. The risk of bacteremia and septicemia is significantly increased in those with chronic graft-versus-host-disease. Treatment with azathioprine in these patients also increases the risk of secondary or recurrent neoplasms. Scleroderma like lesions associated with the chronic form of the disease can cause contractures of joints, affecting movement and ability to perform normal activities.

Transfusion-associated graft-versus-host-disease may have the frequent and possibly fatal complication of bone marrow aplasia. Irradiating blood products before transfusion can prevent this complication. Chronic graft-versus-host-disease may produce lichen planus in the oral cavity. There is a higher risk of these lesions becoming malignant. These oral cancers may have a more aggressive progress and a poorer prognosis.

The severity of acute graft-versus-host-disease is predictive of mortality rates. Outcomes for the disease are also determined by the patient’s response to treatment. Significantly higher mortality rates are seen in patients not responding to treatment or having progression of symptoms despite treatment. This rate may be as high as 75%, compared to 20-25% in those who respond well to treatment [3].

Graft-versus-host-disease occurs only in individuals who have received transplantations, especially of hemopoietic cells from a donor with remnants of the donor T-cells. Symptoms occur when these T-cells recognize the recipient’s tissues as foreign, inflammation and ulceration results. Recipient tissues, particularly skin, liver, and gastrointestinal, are damaged from this process.

Graft-versus-host-disease occurs in 7 to 10% of transplant recipients. The incidence may be as high as 50% in patients receiving stem-cell or bone marrow transplantation [4]. The rate of chronic graft-versus-host-disease is lower in children than in adults.

Acute graft-versus host disease is a substantial post-transplantation problem and is the primary cause of mortality in these patients. Following transplantation, T-cells in the graft tissue, blood, organ, or bone marrow, attack the tissues of the recipient, after identifying host cells as foreign proteins. Even histo-compatible identical donors, siblings or unrelated donors, have minor antigens that are not compatible. Remnant donor T-cells proliferate and become effector cells which identify cells of the recipient as foreign proteins and attack them [3]. This process leads to damage to the recipient’s tissue, especially dermal, gastrointestinal, and liver tissue. This then prompts the recipient’s body to produce inflammatory leukocytes and cytokine. Graft-versus-host-disease occurs in a three step process [3]. The first step actually occurs prior to transplantation. This step involves chemotherapy and/or irradiation of the recipient in preparation for transplantation or to treat an underlying neoplasm or disease. These treatments cause the initial damage to the recipient’s liver, skin, and intestinal mucosa. Step two occurs with the activation and proliferation of the donor T-cells that have been introduced into the recipient’s system through the transplantation or transfusion process. These cells then attack the already damaged recipient tissues. The third phase is the response of the recipient’s immune system with the secretion of inflammatory leukophages and cytokines resulting in an aggressive inflammatory reaction.

Chronic graft-versus-host-disease mimics autoimmune diseases. The process is essentially the same as in acute graft versus host disease but has a delayed development and extended course. The exact reason for this delay or extension of symptoms in the chronic form is not yet clearly understood. Chronic graft-versus-host-disease affects most organs of the body. Skin and oral symptoms are the most common. Eyes, gastrointestinal mucosa, lungs, joints, and liver are often affected as well.

The primary intervention for acute graft-versus-host-disease is prevention. A 6 month course of cyclosporin A or tacrolimus, together with a short-course of methotrexate, should precede or follow transplantation. Better typing and correlation of donor and host to prevent dissimilarities may do much to preventing the disease.

Graft-versus-host-disease (GVHD) is a common complication in the transplantation of cells, tissue, or organs. It is most often associated with stem cell or bone marrow transplantation, or blood transfusions [1]. Graft-versus-host-disease is a progressive systemic disorder involving tissue damage to various organs, particularly, liver, skin and intestinal mucosa, of the recipient’s body. Graft-versus-host-disease is an immune response disorder caused by an adverse interaction between the T-cells of the donor graft and the recipient’s tissue [2]. The disorder occurs when residual donor T-cells in the graft are activated and attack recipient tissues primarily the skin, liver, gastrointestinal tract, and lungs. There are two forms of the disease, acute and chronic. Acute graft-versus-host-disease presents within 20 to 40 days of transplantation [1]. Chronic graft-versus-host-disease occurs more than 100 days after transplantation and includes additional symptomology.

Acute graft-versus-host-disease is staged from 1 to a high of 4. Patients with grade 4 graft versus host disease usually have a poor prognosis. The occurrence and severity of the disorder depends on the source of donor graft [3]. The incidence is significantly higher with unrelated donors than in related/sibling donors.

What is graft-versus-host-disease?

Graft-versus-host-disease (GVHD) is a complication that can occur after transplantations, stem cell or bone marrow transplants, and transfusions, in which the newly transplanted donor cells attack the transplant recipient's tissues. It results is inflammation, ulceration, and damage to the patient’s skin, liver, and mucous membranes of the mouth, esophagus, and intestines. There are two types of graft-versus-host disease, acute and chronic. Symptoms in both forms may be mild or severe. Acute graft-versus-host-disease happens within 3 months of transplant. The chronic form occurs more than 3 months after transplant.

What are the symptoms of graft-versus-host-disease?

Symptoms of acute graft-versus-host-disease include:

• Itchy, red skin rash
• Diarrhea, abdominal pain and cramping
• Nausea and vomiting
• Dry irritated eyes
• Jaundice: yellowing of skin or whites of eyes

Symptoms of chronic graft-versus-host-disease are:

• Conjunctivitis (Red irritated eyes)
• Dry mouth, white patches of mucous membrane
• Skin rash, skin thickening
• Fatigue, muscle weakness
• Chronic cough, shortness of breath
• Loss of appetite, weight loss

What causes graft-versus-host-disease?

Graft-versus-host disease is caused when T-cells in the donor graft are activated after transplantation. Once activated these cells mistakenly recognize the cells of the recipient as foreign proteins and attack then. The host tissue, primarily skin, mucous membrane of mouth and intestinal tract, and liver are damaged. The recipient’s body responds with a system wide inflammatory reaction resulting in swelling, ulceration, and cellular death. Graft-versus-host disease does not occur when someone receives his or her own cells during a transplantation or transfusion.

Who gets graft-versus-host-disease?

Tissue and cells from possible donors are checked before the transplantation. Donor and recipient are matched as closely as possible. The closer the match the less likely graft versus host disease will occur. The chance of graft-versus-host-disease is:

• Low when donor cells are from an identical twin
• Incidence is 30 - 40% with a related donor
• Incidence increases to 60 - 80% with unrelated donor

At highest risk of developing graft-versus-host-disease are:

• Patients who do not receive prophylaxis
• Elderly patients
• Recipients of stem cells that are not identical
• Recipients of grafts from unrelated donors
• Newborns and fetuses
• Recipients with immunodeficiency disorders
• Patients on immunosuppressive chemotherapy

How is it diagnosed?

There is no specific tests for the diagnosis of graft-versus-host disease. However, a biopsy of the skin, mucus membranes, intestinal tract, or liver may help confirm the diagnosis. Some lab and imaging tests can be helpful in the monitoring of the disease and its complications.

How is graft-versus-host-disease treated?

After a transplant, usually, all recipients take medications to suppress their immune system. This reduces the incidence and severity of graft versus host disease. These and other drugs are continued after transplantation to continue prevention. The primary treatment once graft-versus-host disease has been diagnosed is high-dose corticosteroids like prednisone. Approximately a third of patients do not respond to these drugs. There are other drugs now being used in resistant cases.

What are the complication of graft versus host disease?

During the acute phase of graft-versus-host disease, patients are at risk for dehydration due to severe diarrhea and vomiting. Severe anemia may also result from gastrointestinal bleeding. Graft-versus-host-disease may cause permanent damage to affected tissues, liver, skin, mucous membranes of intestinal tract, and lungs. This damage is a result of inflammation. Those with the disorder are at risk for severe, often life threatening infections as a result of high-dose, long-term immunosuppressive drugs.

What can we do to prevent the complications?

In the acute phase, resting of the gastrointestinal tract may be necessary to reduce and resolve the diarrhea. However, maintaining hydration is crucial. A gradual progressive diet is recommended, clear liquids to bland diet. Avoid exposure to the sun and use greater than SPF 30 sunblock. Good skin care is essential to prevent skin infections. Moisturizing lotions or creams help prevent skin breakdown. Avoid unnecessary exposure to infections while they are receiving highly immunosuppressive treatment. Regular exercise to maintain muscle tone and activity tolerance.

1. Jacobsohn DA, Chan GW, Chen AR. Current Advances in the Treatment of Acute and Chronic Graft-versus-Host Disease. Blood and Marrow Transplantaion Reviews. 2007;17:4–14.
2. Socié G, Blazar BR. Acute graft-versus-host disease: from the bench to the bedside. Blood. 2009 Nov 12. 114(20):4327-36.
3. Deeg HJ, Henslee-Downey PJ. Management of acute graft-versus-host disease. Bone Marrow Transplant. 1990 Jul;6(1):1-8.
4. Jacobsohn DA, Vogelsang GB. Acute graft versus host disease. Orphanet Journal of Rare Diseases. 2007;2:35. doi:10.1186/1750-1172-2-35.
5. Burt RK, Hess A, Deeg HJ. How to identify GVHD. Contemp Oncol. 1993. 19-34.
6. Mollee P, Morton AJ, Irving I, et al. Combination therapy with tacrolimus and anti-thymocyte globulin for the treatment of steroid-resistant acute graft-versus-host disease developing during cyclosporine prophylaxis. Br J Haematol. 2001 Apr. 113(1):217-23.
7. Levine JE, Paczesny S, Mineishi S, Braun T, Choi SW, Hutchinson RJ, et al. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood. 2008 Feb 15. 111(4):2470-5.