In short

When donated stem cells see the body they are meant to heal as a threat, they can launch an attack that affects multiple organs and systems, creating a challenging condition that requires careful management and support.

What is graft versus host disease?

Graft versus host disease (GvHD) is a serious complication that can happen after an allogeneic transplant—a procedure where a person receives stem cells or bone marrow from another person (a donor). During this type of transplant, healthy hematopoietic stem cells (immature blood cells) from a donor are placed into the recipient's body, where they eventually become mature blood cells.

People may need donor stem cells if they have problems with their blood cells, such as cancers like leukemia or lymphoma, or other bone marrow failure diseases like aplastic anemia.

In GvHD, the donated stem cells (the graft) view the recipient's body cells (the host) as foreign invaders and begin to attack them. This is why the condition is called "graft" versus "host." The donated cells do this because they contain immune cells called T lymphocytes (or T cells) that recognize the recipient's tissues as different due to differences in proteins called human leukocyte antigens (HLA).

GvHD is a common complication following allogeneic stem cell transplant. The condition occurs because normally, immune system cells recognize proteins on our body's cells and don't attack them. We inherit these HLA proteins from our parents, and apart from identical twins, HLA is unique to each person. When donor cells have different HLA patterns than the recipient, they may see the recipient's cells as a threat.

Types of graft versus host disease

There are two main types of GvHD. Healthcare providers now diagnose the specific type based on symptoms and clinical signs, in addition to when the symptoms begin.

Acute graft versus host disease

Acute GvHD (aGvHD) occurs shortly after transplant, usually within the first 100 days. However, symptoms of aGvHD may also start later. This form most often affects the skin, gastrointestinal (GI) tract (including the bowel and stomach), or liver.

The National Institutes of Health recognizes several patterns of acute GvHD. Acute classic GvHD presents within 100 days of transplantation with typical clinical features. Persistent, recurrent, or late-onset acute GvHD shows the same features but appears after 100 days of transplantation.

Acute GvHD is graded based on the severity of symptoms, ranging from grade 1 (mild symptoms) to grade 4 (very severe symptoms).

Chronic graft versus host disease

Chronic GvHD (cGvHD) can appear any time after an allogeneic transplant, but most cases start within two years. Classic chronic GvHD presents after 100 days of transplant with classic clinical features. Chronic GvHD might affect the skin, mouth, liver, lungs, GI tract, muscles, joints, or genitals.

Chronic GvHD usually starts 100 or more days after an allogeneic stem cell transplant and can last a few months or a lifetime. It can happen right after acute GvHD, after a time with no symptoms, or even if a person hasn't had acute GvHD.

Overlap syndrome

Sometimes the two types can overlap. This is called overlap syndrome, which may occur at any time after transplant with features of both acute and chronic GvHD.

As an allogeneic transplant recipient, a person might experience either form of GvHD, both forms, or neither.

What causes graft versus host disease?

With GvHD, donor stem cells from an allogeneic stem cell transplant attack the recipient's body because they see the recipient's cells as a threat.

Normally, blood cells in the immune system keep people free of infection by fighting invaders that don't belong, like viruses and bacteria. These blood cells don't attack the body's own cells because they recognize proteins on them called human leukocyte antigens (HLA). When donor cells have different HLA patterns, they may identify the recipient's cells as foreign and begin to attack them.

This condition arises when immunocompetent T lymphocytes from the donor graft recognize the recipient's tissues as foreign due to histocompatibility differences and initiate an immune response against them.

Who is at risk?

It is difficult to say exactly who will develop GvHD after a transplant and how severe it will be. Some people who have an allogeneic transplant never get GvHD. The closer the donor's stem cells match the recipient's, the less likely it is that GvHD will develop.

Several factors can increase the risk of GvHD:

The donor is not related to the recipient
The best available donor is still a slight mismatch—the donor will be as close an HLA match as possible
The donated stem cells or bone marrow contain high numbers of T cells (though this may also lower the chance of relapse)
The recipient or donor is older—the older the person, the higher the risk
The donor is a different sex than the recipient—this is particularly true if a male has a female donor who has had children or been pregnant in the past
The recipient doesn't have a very common virus called cytomegalovirus (CMV negative) but the donor is CMV positive
The recipient has a donor lymphocyte infusion (DLI), using white blood cells from the donor—this might be done if the disease comes back after a donor transplant
The donor is not related to the recipient or isn't a close match
The recipient hasn't taken drugs that suppress the immune system after transplant

The chance of GvHD is around 35% to 45% when the donor and recipient are related, and around 60% to 80% when the donor and recipient are not related.

Symptoms of graft versus host disease

Symptoms of GvHD range from mild to moderate to severe (potentially fatal). The symptoms differ between acute and chronic forms of the disease.

Acute GvHD symptoms

Symptoms of acute GvHD most often affect the skin, gastrointestinal (GI) tract, or liver.

The most common symptom of skin acute GvHD is a rash or reddened areas on the skin similar to a sunburn. The skin may feel painful or itchy. These rashes usually start on the neck, shoulders, ears, and the palms of the hands and soles of the feet. The rash can spread to other parts of the body.

The most common symptoms of GI acute GvHD are nausea, vomiting, and diarrhea. Symptoms can be mild or severe enough that a person may need to visit the hospital for treatment.

Common acute symptoms include:

Rash and/or itching
Burning and redness of the skin on the palms of the hands or soles of the feet
Blisters and peeling skin
Diarrhea
Nausea and vomiting
Abdominal cramping, loss of appetite, cramping or abdominal pain
Jaundice (yellow discoloration of the skin and/or eyes)
Enlarged liver, liver tenderness, abnormal liver enzymes or liver failure
Increased risk for infections

Chronic GvHD symptoms

Chronic GvHD most commonly affects the skin, liver, GI tract, and lungs, but it can affect any body part or almost any part of the body. In some cases, chronic GvHD can permanently damage an organ.

Symptoms may include:

Rash and/or itching
Skin tightness and swelling, skin problems such as dryness, peeling, darkening, hard texture and feeling tight
Hair loss on the head and body
Dry mouth with or without mouth ulcers, white patches inside the mouth, and sensitivity to spicy foods
Mouth sores
Gum disease
Dry or gritty feeling in the eyes, dry eyes that may have a burning or gritty feeling
Vision changes
Diarrhea, loss of appetite, stomach cramps
Nausea and vomiting
Yellow discoloration of the skin and/or eyes (jaundice)
Shortness of breath (dyspnea), difficulty breathing
Dry, persistent cough
Fatigue
Muscle weakness, cramping or pain
Pain in muscles and joints, decreased range of motion in joints
Vaginal dryness, itchiness or pain with intercourse
Itchy penis or scrotum or pain with intercourse
Weight loss
Infections
Brittle hair and premature graying
Damage to sweat glands

How is graft versus host disease diagnosed?

The healthcare team will check regularly for early signs of GvHD, especially after a transplant. It's important to tell the healthcare team about any symptoms.

Several lab and imaging tests can be done to diagnose and monitor problems caused by GvHD. These may include:

X-ray abdomen
CT scan abdomen and CT chest
Liver function tests
PET scan
MRI
Capsule endoscopy
Liver biopsy

A biopsy of the skin or mucous membranes in the mouth may also help confirm the diagnosis.

Treatment and management

There is good evidence for initial treatment of both acute and chronic forms of the disease with corticosteroid therapy. However, the most effective approach to steroid-refractory disease (disease that doesn't respond to steroids) remains controversial, with current practice based mainly on smaller studies and varying considerably between local institutions.

Treatment for acute GvHD

For skin GvHD of stage I or II, observation or a trial of topical corticosteroids (such as triamcinolone 0.1%) may be used. Systemic treatment begins in patients with grade II-IV acute GvHD.

Treatment consists of continuing the original immunosuppressive prophylaxis (such as cyclosporine or tacrolimus) and adding methylprednisolone. Doses have been in the range of 1-60 mg/kg, but the most common starting dosage is 2 mg/kg per day given in 2 divided doses. The median time to resolution of acute GvHD is 30-42 days.

Other therapies include antithymocyte globulin (ATG), sirolimus, mycophenolate mofetil (MMF), anti-interleukin-2 (IL-2) receptor, and other agents. These can be used alone or in combination. No data from well-conducted controlled trials have shown the superiority of any of those over any other therapies.

Treatment for chronic GvHD

The main drug combination given to prevent GvHD or decrease its severity is cyclosporine and methotrexate. Alternating cyclosporine and prednisone every other day is a common treatment.

Other drugs used in combination or alone include:

Tacrolimus
Mycophenolate
Sirolimus
Thalidomide
Azathioprine
Pentostatin
Infliximab
Dacluzumab
Ibrutinib (for refractory chronic GvHD)

Immunosuppressive therapies

People may need to take drugs that suppress the immune system to prevent or treat GvHD. These drugs may be taken for months or years after an allogeneic transplant.

Antibiotics, antifungal, and antiviral drugs may be given to reduce the risk of infection while GvHD is being treated with drugs to suppress the immune system. The suppressed immune system puts a person at high risk for developing many infections.

Other treatments

Extracorporeal photopheresis (ECP) is an immunomodulatory procedure in which lymphocytes are collected and mixed with a medication that makes them susceptible to cell death when exposed to ultraviolet light. The lymphocytes are then returned to the patient. ECP has been used as part of a conditioning regimen with promising results.

Eye drops, such as artificial tears, can be used for dry eyes. People should also protect themselves from the sun's UV rays.

Supportive care

Timely diagnosis, multidisciplinary working, and good supportive care, including infection prophylaxis, are clearly important in optimizing response and survival in patients with GvHD.

Prevention strategies

To help prevent GvHD, doctors may remove some of the immune cells that cause GvHD before the stem cell transplant. This is called T-cell depletion.

Primary prophylaxis for acute GvHD includes the use of cyclosporine for 6 months and short-course methotrexate in T-cell-replete allogeneic hematopoietic cell transplantation. Cyclosporine levels should be kept above 200 ng/mL. Tacrolimus is frequently substituted for cyclosporine, especially in unrelated-donor transplantation, because it may improve the control of GvHD, though not survival.

Antithymocyte globulin (ATG) given before transplant significantly reduces the risk of grade III or IV acute GvHD and extensive chronic GvHD, but it does not alter survival, possibly because of the increased risk of infection.

Before a transplant, both the recipient and donor have blood tests to check how closely their HLA matches. This test is called tissue typing. If the recipient and donor have very similar HLA, this lowers the chance of GvHD. The more differences there are between the HLA patterns, the more likely GvHD is to develop.

Living with graft versus host disease

Living with GvHD can be an emotionally difficult experience for both the person affected and their family. After transplant, everyone wants to resume a normal life, but GvHD can make that difficult for a time.

Emotional challenges

It's normal to feel sad or anxious while dealing with GvHD. Physical changes, some of the drugs used to treat GvHD, fatigue, and sleep problems can cause depression, confusion, anxiety, mood swings, or exaggerated feelings of anger, excitement, or sadness. It's important to let the doctor know about any of these symptoms.

Living with GvHD sometimes feels like an emotional roller coaster, with ups and downs and unexpected twists and turns. It can be challenging to have to deal with a new problem after having made it through transplant.

Chronic GvHD can be very difficult to cope with, especially when a person has been through so much treatment. Dealing with long-term, uncomfortable symptoms after transplant can be hard to accept. People may feel very low (depressed) and anxious and might need support during this time.

Coping strategies

Figuring out how to adjust to physical, social, and emotional changes takes time. The goal is to learn to manage GvHD without being defined by it. It helps to:

Take each day as it comes, one day at a time
Focus on what can be done, rather than what can't
Build flexibility into plans since it's not always known how a person will feel
Notice small things that bring joy and pleasure
Engage in non-medical activities that help create a sense of normalcy and remind the person of who they are

Talking about feelings

If someone has GvHD, it's important not to ignore or downplay feelings. Finding an outlet to express and process feelings can decrease stress, facilitate problem-solving, and help move forward in a healthy manner.

Talking with a social worker, psychologist, psychiatrist, or pastoral counselor often helps, especially those who have experience working with patients who live with GvHD and their caregivers.

Talking with others who have been down the same path can be especially helpful. Speaking with other survivors who "get it" may make a person feel less alone. In addition, they can share information and coping strategies that they found useful.

Meditation and relaxation

Patients with GvHD often find that meditation, guided imagery, and relaxation techniques help them cope with the stress of living with GvHD. Practicing mindfulness—living in the moment, acknowledging and accepting feelings—can also be beneficial.

Physical challenges

Chronic skin GvHD, steroid treatment, eye problems, and weight loss can all affect how someone looks. This might affect self-esteem and how a person thinks others see them. GvHD of the muscles and joints can be painful and affect mobility. Gentle exercises to improve range of movement can help.

People might also feel very tired and lethargic or might be breathless if they have GvHD of the lung, which can make them feel anxious. Breathing and relaxation techniques may help.

Relationships and quality of life

The physical and emotional changes might affect relationships and sex life. There are things that can be done to manage this. It might help to tell a partner how the person is feeling about themselves and what their worries are.

Chronic GvHD can affect quality of life. The length of time a person has chronic GvHD can vary. A lot of people see a gradual improvement over a few months, but for some it can last longer. The average length of time is between 1 and 3 years. Some people can have it for longer.

Practical matters

Practical things people and families might need to cope with include money matters, financial support (such as benefits, sick pay, and grants), work issues, and childcare. Talking to a doctor or specialist nurse to find out who can help is important. Getting help early with these things can mean that they don't become a big issue later.

Getting support

Getting information about GvHD can help people cope, so they know what to expect. Doctors and specialist nurses can give advice. It's important to take some time out to look after oneself. There are organizations that can help with practical and emotional support.

Graft versus host disease

Clinical trials for Graft versus host disease