Graft-versus-Host Disease (GVHD) is a potentially lethal side effect that occurs in many allogeneic transplant patients. GVHD happens when mature transplanted donor T- cells recognize the patient’s tissue as ‘non-self’ and start attacking the patient’s body, causing skin damage, gastrointestinal tract malfunction, liver injury and other organ system impairment. Some patients who experience severe GVHD may even require tube feeding as their esophagus and mouth have been damaged beyond repair or a lung transplant is necessary as the lungs are too damaged by GVHD.
GVHD is not rare. Up to 70 percent of transplant recipients develop acute GVHD, which crops up within the first few months of treatment, and up to 40 percent get chronic GVHD, the form that appears more than 100 days post-transplant. The effects of GVHD can be seen throughout the body, affecting almost any organ and manifesting through rashes and skin thickening, joint pain and stiffness, eye dryness and irritation, diarrhea, jaundice, mouth sores and ulcers, and severe lung dysfunction. The mortality rate for GVHD with unrelated donor transplants is approximately 20%; for HLA-matched sibling transplants this is still as high as 17%.
How does GVHD develop?
The donated stem cells will contain some mature T-cells. These cells help fight infections, and attack and destroy cells they see as foreign and potentially harmful – for example bacteria and viruses. Normally, T-cells don’t attack a person’s body cells (thereby causing GVHD), as they recognize proteins on these cells called HLA (human leukocyte antigens), which are unique to each person. If the patient and donor have very similar HLA this lowers the chance of GVHD. However, the more differences there are between the patient’s HLA and the donor’s, the more likely the patient will develop GVHD. The GVHD may affect different areas of the body. Most commonly it affects the skin, digestive system (including the bowel and stomach) or the liver.
The pie charts show causes of death among patients who received a cell graft from an HLA-matched sibling or an unrelated donor. Data is from the Center for International Blood and Marrow Transplant Research, for allogeneic hematopoietic stem cell transplants performed in 2012-13 (Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015, available from: http://www.cibmtr.org)
Types of GVHD
GVHD can be grouped according to when it develops after the transplantation into acute and chronic GVHD. Symptoms in both acute and chronic GVHD range from mild to severe.
View pictures of GVHD here (WARNING: May contain some disturbing images. Viewer discretion advised!).
Acute GVHD generally starts within 100 days after transplantation, but it can sometimes happen after this time. It often starts with a rash on the ears or face or the palms of the hands and soles of the feet. The rash may be itchy or painful. It may also affect the mouth, digestive system and liver. This can cause diarrhea, sickness, loss of appetite and yellowing of the skin. The severity of GVHD depends on the extent of genetic differences between patient and donor. Acute GVHD can occur soon after the transplantation, typically in the first one hundred days. It is graded from I (mildest) to IV (most severe). Grade III/IV acute GVHD is regarded as life-threatening.
Stages of acute GVHD
|Stage 1 (mild)||a skin rash over less than 25% of the body|
|Stage 2 (moderate)||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, peeling skin, and severe liver, stomach, and intestinal problems|
The incidence of cGVHD has continued to increase over time, and approximately 30-70 percent of post allogenic transplant patients will develop cGVHD (Arai et al., 2015; Grube et al., 2016). Chronic GVHD starts more than 100 days after transplantation. It is more likely to develop after acute GVHD, but it can also occur without previous development of acute GVHD. Like acute GVHD, it may affect the skin, digestive system, liver or mouth. But it can also affect other parts of the body, such as the eyes, lungs, vagina and joints. Chronic GVHD tends to manifest itself only as of the fourth month after a transplant. Chronic GVHD is more likely to occur in older patients, or in patients who previously had acute GVHD. Chronic GVHD is graded as mild, moderate or severe, can persistent for years and can be severely incapacitating and impact quality of life.
What are the signs and symptoms of GVHD?
Acute GVHD and chronic GVHD are distinct diseases. One common factor is that they both increase the patient’s susceptibility to infection. The symptoms of GVHD can be difficult to cope with. In some cases, GVHD is a serious, even life threatening, problem.
|Acute GVHD||Chronic GVHD|
Current treatment of GVHD
Currently, multiple immunosuppressive agents are used to prevent GVHD, such as cyclosporine, tacrolimus, mycophenolate mofetil and sirolimus. Even with the use of these medications, the incidence of severe (grade III/IV) GVHD as a result of HSCT is approximately 30% (Jagasia et al., 2012). If GVHD develops, treatment relies on administrating glucocorticoids such as methylprednisolone or prednisone, antithymocyte globulin, monoclonal antibodies, mycophenolate mofetil, sirolimus and oral nonabsorbable corticosteroids.
Treatment for patients who do develop GVHD depends on the severity of the disease. Mild cases with only skin involvement of acute GVHD may settle without treatment. More severe acute or chronic GVHD predisposes the patient to infection and overwhelming sepsis (blood poisoning) is the main cause of death in patients with GVHD.
Patients may need to continue taking such medications for many months or years after transplantation. GVHD does not always respond to these treatments and can still result in death, and many deaths related to GVHD occur as a consequence of opportunistic infections that develop in patients with suppressed immune systems.
Quality of life after GVHD
Quality of life is a multi-dimensional construct composed of several related domains including physical, emotional, social, and role functioning, as well as a person’s overall evaluation of his or her well-being and ability to function. It has been shown that GVHD has an adverse impact on the quality of life compared to patients who did not develop GVHD.
Chronic GVHD requires continued, possibly life-long, immunosuppressive therapy plus other modifying agents. GVHD developed on the skin may result in severe rash and ulcers, open skin and damages as if the skin is suffering from constant severe burns. These patients may require continuous wound debridement and skin grafting. GVHD can also result in the inability to move joints due to the extreme stiffening of muscle and skin, resulting in surgical release of the contracted joint. These surgeries may have to be repeated throughout the patient’s life.
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