Symptoms of Graft-Versus-Host Disease (GvHD)

Graft-versus-host disease (GvHD) is a complication of an allogeneic stem cell or bone marrow transplant, in which cells from a donor trigger an autoimmune-like response in the recipient, causing the body to attack its own tissues. An allogeneic transplant is one in which cells are donated.

Depending on which organs the immune system attacks, GvHD can cause symptoms ranging from rash, diarrhea, and hepatitis to potentially life-threatening bacterial, fungal, viral, or parasitic infections.

GvHD symptoms are broadly classified as being either acute (occurring within the first 100 days of a transplant) or chronic (occurring after 100 days).

Acute Symptoms

Acute GvHD, also known as fulminant GvHD, affects between 40% and 70% of people who undergo an allogeneic stem cell or bone marrow transplant.

Acute GvHD is a condition in which the donated cells have a more immediate response to the cells and tissues of the recipient, which they regard as "foreign." When this occurs, the donor cells will trigger the release of defensive white blood cells, called T-cell lymphocytes, to neutralize the perceived threat. Even if the donor is genetically matched, acute GvHD can still occur.

Acute GvHD typically affects a triad of organ systems (although it can involve other organ systems as well). The three most common by order of frequency are:

• Gastrointestinal: Occurring in 75% of acute cases
• Skin: Occurring in 70% of acute cases
• Liver: Occurring in 44% of acute cases

The acute symptoms will often resolve within a year or so of the transplant when the body starts to produce its own white blood cells from the donor cells. But some people have to manage the condition for many years with drugs that temper the immune overreaction.

Cutaneous

Acute GvHD usually starts with the sudden outbreak of redness, burning, pain, and rash on the palms, soles, face, ears, and shoulders. These initial symptoms can sometimes progress and spread over the entire body. 

The outbreak, referred to as an erythematous maculopapular morbilliform eruption, is characterized by flat, reddened areas of skin populated with tiny, measle-like bumps. The pattern of the rash is often described as lace-like.

Gastrointestinal

Acute GvHD can trigger severe gastrointestinal inflammation and the sloughing (shedding) of mucosal tissues from the lining of the digestive tract. This can adversely alter the bacterial flora in the gut, often leading to severe Clostridioides difficile colitis (colon inflammation). Tissues of the mouth and gums can also be affected.

The gastrointestinal symptoms of acute GvHD may include:

• Nausea and vomiting
• Abdominal cramps
• Indigestion and heartburn
• Bloating
• Greenish, watery diarrhea
• Bloody stools
• Mouth pain
• Dry mouth
• Taste changes
• Loss of appetite

Hepatic

The hepatic (liver) symptoms of acute GvHD commonly occur with skin and gastrointestinal symptoms; they rarely occur on their own. The development of hepatic symptoms are strongly suggestive of high-grade GvHD requiring aggressive treatment.

In people with acute GvHD, the immune assault will trigger many of the characteristic symptoms of hepatitis (liver inflammation), including:

• Pain and swelling in the upper right quadrant of the abdomen (usually mild)
• Chronic fatigue
• Dark urine
• Chalk-colored stool
• Itching
• Nausea
• Loss of appetite

On occasion, jaundice (the yellowing of the eyes and skin) may develop, although it will usually be mild to vague.

Chronic Symptoms

The chronic symptoms of GvHD are broadly defined as those that develop after 100 days of a transplant. Most cases will develop within the first year, although some present with symptoms well after the first year. All told, between 30% and 70% of allogeneic transplant recipients will develop chronic GvHD, albeit to varying degrees.

Chronic GvHD is defined by more than just the timing of symptoms. It is characterized by the ongoing or recurrent assault of organs by the immune system. As a result, the cutaneous, gastrointestinal, and hepatic symptoms tend to be worse. Other organ systems may also be affected, including the eyes, joints, lungs, muscles, and genitals.

Chronic GvHD may develop on its own or be preceded by acute GvHD. In addition, there may be an overlap of symptoms—such as more chronic symptoms occurring within 100 days or cute symptoms occurring before 100 days—which doctors aptly describe as "overlap syndrome."

Cutaneous

As with acute GvHD, chronic GvHD will often present with cutaneous symptoms first. The maculopapular rash will typically start on the palms and soles, spreading outward to affect other parts of the body. In addition to pain, burning, and redness, there may also be blistering and the peeling of skin similar to a severe sunburn.

Over time, the injury to the skin can cause hypopigmentation (loss of skin color), hyperpigmentation (darkened skin), and sclerotic features (including skin tightness, swelling, and an exaggerated response to cold). Damage to the sweat glands can exacerbate these symptoms, leading to chronic xerosis (skin dryness).

The nails may also be affected by chronic GvHD, causing unsightly ridges on the nail plate as well as the splitting of nails and nail loss. Hair loss is also known to occur as sclerosis causes hair follicles on the scalp to harden and close.

Gastrointestinal

Many of the gastrointestinal symptoms of chronic GvHD are similar to those of acute GvHD, and there is currently no consensus as to which features differentiate acute or chronic disease.

Generally speaking, chronic GvHD suggests greater damage to mucosal tissues in the gastrointestinal tract. The ongoing injury combined with the build-up of scar tissue can lead to severe dysphagia (difficulty swallowing) and early satiety (feeling of fullness after eating) as the esophagus and stomach lose their flexibility and motility. Weight loss is a common consequence.

Hepatic

As with acute GvHD, hepatic symptoms of chronic GvHD are associated with poorer outcomes. When liver symptoms develop, they are most likely to coincide with not only skin and gastrointestinal tract symptoms but eye symptoms as well.

Compared to acute GvHD, the hepatic symptoms of chronic GvHD tend to be more overt, often manifesting with severe hepatomegaly (liver enlargement), vomiting, and jaundice.

Despite the fact that chronic GvHD can cause significant liver fibrosis (scarring), it is rare for it to progress to cirrhosis.

Other Symptoms

Chronic GvHD can affect other organ systems, most commonly the eyes but also the lungs, joints and muscles, genitals, and nervous system. Symptoms vary by organ system and may include:

• Eyes: Dry eyes, blurred vision, photophobia (extreme light sensitivity), and blepharitis (eyelid inflammation)
• Lungs: Shortness of breath, wheezing, and persistent dry cough
• Joints and muscles: Arthralgia (joint pain), myalgia (muscle pain), loss of muscle strength, stiff joints, and the loss of range of motion
• Genitals: Vaginal stenosis (narrowing) in women, urethral stricture in men, and pain with intercourse
• Nervous system: Paresthesia (burning or prickly sensations) and neuralgia (sharp, shooting nerve pains)

Complications

Graft-versus-host disease is associated with a high risk of infection, due in part to the immunosuppressive drugs used to prevent GvHD in transplant recipients and the immunosuppressive effects of corticosteroid drugs used to treat acute and chronic GvHD. Both can dampen the natural immune response and leave the body open to an array of opportunistic infections.

According to a 2019 study in Bone Marrow Transplantation, infections are among the primary causes of death in people with GvHD. Bacterial and fungal infection are the main culprits, although the exact infective agent is often unidentified.

Other complications of chronic GvHD are pericarditis (inflammation of the membrane surrounding the heart) and pleuritis (inflammation of the membranes surrounding the lungs). These conditions only occur in 1.8% of cases but can lead to severe pericardial and pleural effusion (in which the space between the membranes and organ fills with an excessive amount of fluid).

Severe pericardial effusion has been known to cause potentially life-threatening cardiac tamponade in people with GvHD.

A Word From Verywell

Although a significant number of people who undergo an allogeneic stem cell or blood marrow transplant will develop GvHD, not everyone does. Even if it does occur, treatments are improving every day, extending the life and quality of life of those living with GvHD.

Today, the five-year survival rate for people with GvHD is roughly 50%, meaning that half of all people will live for at least five years following the development of symptoms.

By adhering to prescribed treatments and maintaining a healthy lifestyle (including routine exercise, good nutrition, daily skincare, and stress reduction), you'll be better able to cope with GvHD as well as the treatments used to manage the condition.