Acute Graft Versus Host Disease

Acute graft versus host disease is a serious complication that can occur after a stem cell transplant, when the donated immune cells mistake the recipient’s body as a threat and begin to attack it. This condition typically appears within the first three months after transplant and affects thousands of patients each year.

Table of contents

• What Is Acute Graft Versus Host Disease
• What Causes This Condition
• Who Is Affected
• Signs and Symptoms
• How It Is Diagnosed
• Treatment Options
• Living With the Condition

What Is Acute Graft Versus Host Disease

Acute graft versus host disease is a condition that occurs when immune cells from transplanted tissue recognize the recipient’s body as foreign and attack its cells^[1]. In this context, graft refers to the transplanted or donated tissue, while host refers to the recipient’s tissues^[1].

This condition is a common complication following allogeneic hematopoietic stem cell transplantation, which is a procedure where stem cells from a donor are transplanted into a patient^[3]. The donated stem cells, also called immature blood cells, eventually become mature blood cells that help treat serious conditions like leukemia, lymphoma, or aplastic anemia^[2].

Acute graft versus host disease is caused by the recognition and destruction of the recipient’s tissues and organs by the donor immune cells^[3]. This condition usually occurs within the first three months after transplantation, but later onset is possible^[3]. Healthcare providers traditionally classified the disease based on timing, using 100 days after transplant as the dividing line, but more recently they diagnose the specific type based on symptoms and clinical signs in addition to the timing of symptom onset^[2].

What Causes This Condition

Normally, blood cells in your immune system keep you free from infection by fighting invaders that don’t belong, like viruses and bacteria^[2]. These blood cells don’t attack your body’s cells because they recognize a protein on them called human leukocyte antigens, or HLA. Think of HLA as a nametag that identifies a cell as belonging to your body^[2].

In acute graft versus host disease, the donated stem cells view the recipient’s cells as an unfamiliar threat. As a result, the donated cells attack the recipient’s cells^[2]. This happens because of differences in the HLA proteins between the donor and the recipient.

The development of acute graft versus host disease involves a complex process that occurs in three phases^[11]. The process starts with initial tissue damage from the conditioning regimen, which includes chemotherapy or radiation used before transplant. This damage activates the host’s immune cells. In the second phase, donor immune cells become activated when they recognize the recipient’s tissues as foreign. Finally, in the third phase, these activated donor cells cause damage to the recipient’s organs and tissues^[5].

Risk Factors

Several factors can increase the risk of developing acute graft versus host disease^[5]:

• Unmatched donor transplants
• Human leukocyte antigen disparity between donor and recipient
• Sex mismatch between donor and recipient
• Chemotherapy and radiation therapy causing total body irradiation

On the other hand, some factors can lower the risk^[5]:

• Cryopreservation of marrow
• Use of immunomodulators
• Umbilical cord blood as the source of stem cells

Who Is Affected

Acute graft versus host disease affects a significant number of patients who undergo stem cell transplants. About 35% to 50% of patients who receive hematopoietic stem cell transplants will develop acute graft versus host disease^[4]. The exact risk depends on several factors, including the stem cell source, the age of the patient, the conditioning regimen used, and the preventive treatment given^[4].

The occurrence of acute graft versus host disease in patients undergoing transplantation from an HLA-matched sibling ranges between 9% and 50%, with a higher occurrence when donors are not well matched^[5]. Given the number of transplants performed worldwide, approximately 5,500 patients per year can be expected to develop acute graft versus host disease^[4].

Acute graft versus host disease is a major health problem in transplant patients and is associated with high morbidity and mortality^[3]. It remains a major cause of short-term mortality at 100 days and one year after transplantation^[11].

Signs and Symptoms

Symptoms of acute graft versus host disease range from mild to moderate to severe and potentially fatal^[2]. The condition most often affects the skin, gastrointestinal tract, and liver^[2]. These are the targeted organs where the immune attack causes the most damage^[3].

• Skin
• Gastrointestinal tract
• Liver

Skin Symptoms

The most common symptom of skin involvement is a rash or reddened areas on the skin, similar to a sunburn^[2]. 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^[2]. The rash can spread to other parts of the body. In more severe cases, the skin may develop blisters and peeling^[4].

Gastrointestinal Symptoms

The most common symptoms affecting the gastrointestinal tract are nausea, vomiting, and diarrhea^[2]. Patients may also experience crampy abdominal pain^[4]. Symptoms can be mild or severe enough that a patient may need to visit the hospital for treatment^[2]. The condition can irritate the lining of the colon, producing seemingly endless bouts of diarrhea^[13].

Liver Symptoms

When acute graft versus host disease affects the liver, patients may develop jaundice, which is a yellow discoloration of the skin and eyes^[2]. This happens because the disease causes hepatitis and elevation of liver enzymes and bilirubin^[4].

Acute graft versus host disease typically occurs within the first 100 days after transplant, with symptoms usually developing two to three weeks after the procedure^[7]. However, it can also manifest with clinical features of classic acute graft versus host disease after 100 days of transplantation, which is called persistent, recurrent, or late-onset acute graft versus host disease^[1].

How It Is Diagnosed

Acute graft versus host disease is primarily a clinical diagnosis, meaning it is based on physical examination and the pattern of symptoms^[3]. The diagnosis is suspected when a recipient of stem cell transplant develops characteristic signs or symptoms such as dermatitis, cutaneous blisters, crampy abdominal pain with or without diarrhea, persistent nausea and vomiting, or hepatitis with elevation of bilirubin and liver enzymes^[4].

Complementary examinations are performed to exclude other conditions that might cause similar symptoms^[3]. The reason to pursue additional testing, including tissue biopsy, is to help differentiate acute graft versus host disease from other diagnoses that may mimic it, such as viral infection causing hepatitis or colitis, or drug reactions causing skin rash^[4].

Staging and Grading

Acute graft versus host disease is staged and graded by the number and extent of organ involvement^[4]. The grading system ranges from grade 0 to grade IV, with higher grades indicating more severe disease. Patients with grade III or IV acute graft versus host disease tend to have a poor outcome^[4].

Treatment Options

Preventive treatment for acute graft versus host disease is administered to all patients who receive stem cell transplants, although it is not always effective^[3]. The criterion standard for prevention is cyclosporine for six months and short-course methotrexate in transplantation^[10]. Tacrolimus is frequently substituted for cyclosporine, especially in unrelated-donor transplantation, because it may improve the control of the disease^[10].

First-Line Treatment

For patients with mild skin involvement, observation or a trial of topical corticosteroids may be used^[10]. For more significant disease, systemic treatment should begin in patients with grade II to IV acute graft versus host disease^[10].

Steroids are used for first-line treatment^[3]. Generally, the patient is treated by optimizing their immunosuppression and adding methylprednisolone^[4]. Treatment consists of continuing the original immunosuppressive prevention medication and adding methylprednisolone, with the most common starting dosage being 2 mg per kilogram per day given in two divided doses^[10]. The median time to resolution of acute graft versus host disease is 30 to 42 days^[10].

About 50% of patients will have a solid response to methylprednisolone^[4]. In patients who respond to initial therapy, short-term tapering treatment with prednisone is effective and expected to minimize steroid-related complications^[10].

Second-Line Treatment

If patients progress after three days or are not improved after seven days of steroid treatment, they will receive salvage or second-line immunosuppressive therapy^[4]. The Janus kinase 2 inhibitor ruxolitinib is used as second-line treatment^[3].

There is currently no validated standard treatment for acute graft versus host disease that is refractory to steroids and ruxolitinib, and this remains an unmet medical need^[3]. Well-organized clinical trials are imperative to better define second-line therapies for this disease^[4].

Additional Management

Additional management issues include attention to wound infections in skin involvement and fluid and nutrition management in gastrointestinal involvement^[4]. Timely diagnosis, multidisciplinary working, and good supportive care, including infection prevention, are clearly important in optimizing response and survival in patients^[7].

Living With the Condition

Living with acute graft versus host disease can be an emotionally difficult experience for both patients and their families^[12]. After transplant, everyone wants to resume a normal life, but acute graft versus host disease can make that difficult for a time^[12].

It is normal to feel sad or anxious while dealing with the condition^[12]. Physical changes, some of the drugs used to treat the disease, fatigue, and sleep problems can cause depression, confusion, anxiety, mood swings, and exaggerated feelings of anger, excitement, or sadness^[12]. It is important to let your doctor know if you are experiencing any of these symptoms.

Coping With Uncertainty

Living with acute graft versus host disease sometimes feels like an emotional roller coaster, with ups and downs and unexpected twists and turns^[12]. It can be challenging to have to deal with a new problem after having made it through transplant. It is tough not knowing whether things will get worse or better, and how long the condition will last^[12].

The goal is to learn to manage the disease without being defined by it^[12]. Patients are encouraged to take each day as it comes, focus on what they can do rather than what they cannot, build flexibility into their plans, notice small things that bring joy and pleasure, and engage in non-medical activities that help them feel a sense of normalcy^[12].

Finding Support

If you have acute graft versus host disease, it is important not to ignore or downplay your feelings^[12]. Finding an outlet to express and process your feelings can decrease stress, facilitate problem-solving, and help you move forward in a healthy manner^[12].

Talking with a social worker, psychologist, psychiatrist, or pastoral counselor often helps, especially those who have experience working with patients who live with the condition and their caregivers^[12]. Talking with others who have been down the same path can be especially helpful. Speaking with other survivors who understand may make you feel less alone^[12].

Patients with the condition often find that meditation, guided imagery, and relaxation techniques help them cope with the stress of living with acute graft versus host disease^[12].

Long-Term Outlook

About 50% of patients with acute graft versus host disease will eventually have manifestations of chronic graft versus host disease^[4]. The condition can be fatal, which is why timely diagnosis and appropriate treatment are so important^[13].