4 Types of Graft-Versus-Host Disease: Acute, Chronic, Overlap, and Late Acute

There are four main types of graft-versus-host disease (GVHD), classified by their symptoms and when they develop. The two most common types are acute GVHD and chronic GVHD. Acute GVHD comes on suddenly, while chronic GVHD develops slowly and can last a long time.

Some people develop symptoms of acute and chronic GVHD at the same time, a condition known as overlap syndrome. There’s also late acute GVHD, which develops after the typical window for acute symptoms has passed.

This article will discuss these types of GVHD and what causes them. We’ll also cover their symptoms and what to watch for.

If you notice any new or worsening signs of GVHD, talk to your oncology or transplant team. They can run tests to confirm the diagnosis and start a treatment plan.

Acute GVHD develops in people who have recently had an allogeneic stem cell transplant. Also known as an allogeneic bone marrow transplant, this procedure uses healthy stem cells (cells that help make blood) from a donor. These donated cells replace damaged or diseased blood-forming cells, helping your body make healthy blood cells again.

Allogeneic stem cell transplants are a treatment option for certain types of blood cancers like lymphoma and leukemia.

GVHD develops when donated T cells recognize the recipient’s healthy cells as foreign and attack them. Studies show that in acute GVHD, these T cells become activated, triggering inflammation that further damages healthy tissues.

What Causes Acute Graft-Versus-Host Disease?

Certain factors raise the risk of acute GVHD. Before a transplant, doctors run tests to check what kind of human leukocyte antigen (HLA) markers you have.

HLA proteins are on most of your cells. They tell your immune system that your cells belong to you. Cells with different HLA proteins may be recognized as foreign and targeted by your lymphocytes (white blood cells).

Everyone has different HLA markers, so it’s important to find out which you have. Stem cell transplants need to come from people with HLA markers that are the same as or similar to yours.

Identical twins have the same markers, while unrelated people can have very close-matching proteins. HLA-mismatched donors raise the risk of GVHD.

According to Blood Cancer United, you’re more likely to develop acute GVHD if:

• Your donor is unrelated, even if they have the same HLA markers as you.
• Your donor isn’t an exact HLA match.
• You or your donor is older.
• You’re male and receive cells from a female donor.

When and Where Does Acute Graft-Versus-Host Disease Develop?

Traditionally, doctors diagnosed acute GVHD when symptoms developed within 100 days (roughly three months) after a transplant. The National Institutes of Health (NIH) updated the guidelines to classify GVHD based on its clinical features rather than timing alone. Although most cases of acute GVHD occur within 100 days, some can develop later.

According to Blood Cancer United, 30 percent to 70 percent of people who have allogeneic stem cell transplants eventually develop acute GVHD. Symptoms most often affect the skin, liver, and gastrointestinal (GI) tract.

You may have mild, moderate, or severe symptoms. Some people even have life-threatening complications.

Skin problems are common and can develop anywhere on your body. Some people notice rashes, while others may see dark patches or areas of discoloration, especially on the palms of their hands or the soles of their feet.

GVHD can also affect your digestive system. Inflammation in your GI tract can cause diarrhea, vomiting, and nausea. In some cases, you may notice red blood in your stool as well.

Acute GVHD of the liver may not cause noticeable symptoms at first, but doctors can find it through blood tests that show high liver enzyme levels. In more serious cases, it can cause jaundice (yellowing of the skin or eyes). If left untreated, acute GVHD can lead to liver failure.

Grading Acute Graft-Versus-Host Disease

Acute GVHD may be mild, moderate, or severe. Once your doctor confirms that you have acute GVHD, they’ll assign different stages. Staging indicates how severe the disease is based on two factors: which organs are affected and how severe your symptoms are (the grade).

Acute GVHD involvement in individual organs is staged from 1 to 4. Stage 1 is the mildest, while stage 4 is the most severe.

After your doctor stages your organs, they’ll grade your overall acute GVHD. The grading is as follows:

• Grade 1 — Mild GVHD, generally involving the skin only
• Grade 2 — Moderate GVHD, potentially involving the skin, liver, or digestive tract
• Grade 3 — Severe GVHD, often involving significant liver or digestive tract symptoms
• Grade 4 — Life-threatening GVHD involving severe organ damage

Chronic GVHD typically develops more than 100 days after your bone marrow transplant. The term “chronic” means long-term — many people diagnosed with this condition have symptoms for many years. Some can even have lifelong problems.

Chronic GVHD varies in severity, affecting some people mildly while causing serious complications in others. Doctors and researchers don’t understand chronic GVHD as well as acute GVHD. Many believe chronic GVHD is more complex and involves more aspects of the immune system.

The long-term inflammation from this condition can affect more organs than acute GVHD. It also raises the risk of fibrosis — abnormal thickening of tissues throughout your body.

What Causes Chronic Graft-Versus-Host Disease?

Studies show there are some risk factors for developing chronic GVHD. If you’ve had acute GVHD before, you’re also more likely to develop chronic GVHD.

How the donated cells are collected can also affect your risk. For example, cells collected from the bone marrow — the spongy tissue inside the bones — are less likely to cause chronic GVHD than those collected from peripheral blood (the bloodstream).

Like acute GVHD, chronic GVHD also affects people who receive transplants that aren’t a perfect HLA match. According to Blood Cancer United, males who receive donor cells from females are also at an increased risk. This is especially true if the female has been pregnant before.

Similarly, age is a risk factor in GVHD. Older recipient and donor age are associated with a higher risk of GVHD.

When and Where Does Chronic Graft-Versus-Host Disease Develop?

From 40 percent to 50 percent of people who receive an allogeneic stem cell transplant develop chronic GVHD. This condition affects many more organs than acute GVHD. Symptoms of chronic GVHD include:

• Mouth problems like open sores (ulcers), dry mouth, and trouble eating and swallowing
• Skin symptoms like rashes, dry skin, thickening around joints, and color changes
• Dry, itchy eyes and blurry vision
• Trouble breathing, coughing, and wheezing
• Nausea, vomiting, and diarrhea
• Hair loss
• Liver issues
• Muscle and joint issues like muscle cramps and weakness
• Problems in the genitals and sexual organs

If you have overlap syndrome, it means you were diagnosed with chronic GVHD while also having acute GVHD symptoms. Studies show that chronic GVHD symptoms in those with overlap syndrome have a major impact on quality of life. This is likely because chronic symptoms affect more organs — including the joints and lungs.

Doctors treat overlap syndrome based on your chronic GVHD symptoms.

Late acute GVHD is a type of acute GVHD that develops more than 100 days after a transplant. It can happen in three ways.

In persistent GVHD, symptoms continue past day 100. In recurrent GVHD, the condition comes back after getting better for a while. Late-onset acute GVHD can develop after day 100.

Doctors treat GVHD with immunosuppressants (medications that weaken the immune system, including corticosteroids like prednisone). These drugs help prevent donor immune cells from attacking the recipient’s cells. Reducing or stopping immunosuppressants can cause acute GVHD symptoms to return.

Always follow your treatment plan and consult your doctor before making any changes.

When To Call Your Doctor

If you’ve had a stem cell transplant, watch for signs of GVHD like rashes, digestive issues, breathing problems, or fatigue. Staying in close contact with your transplant team helps you catch and manage symptoms early. If you notice any changes, call your doctor right away so they can adjust your treatment as needed.