Graft-Versus-Host Disease

What is Graft-Versus-Host Disease?

Graft-versus-host disease (GVHD) is a condition that happens when immune cells from transplanted tissue see the recipient’s body as foreign and attack its cells. In simple terms, the word ‘graft’ refers to transplanted or donated tissue while ‘host’ relates to the recipient’s own tissues. GVHD often occurs after a particular type of transplant known as an allogenic hematopoietic stem cell transplant.

GVHD is typically classified based on when it presents, either as acute or chronic. It is considered acute if symptoms occur within 100 days of the transplant and chronic if symptoms occur after 100 days. This system for categorizing GVHD comes from the National Institutes of Health (NIH) and includes:

• Acute classic GVHD, which shows symptoms within 100 days of the transplant typical of acute GVHD.
• Persistent, recurrent, or late-onset acute GVHD, which presents with symptoms of classic acute GVHD but occurs after 100 days of transplantation.
• Classic chronic GVHD, which presents after 100 days of transplant with classic symptoms of chronic GVHD.
• Overlap syndrome, which can happen at any time post-transplant and features symptoms of both acute and chronic GVHD.

What Causes Graft-Versus-Host Disease?

Graft Versus Host Disease (GVHD) is a complex health issue that can occur after transplantation procedures. It happens when the donor’s immune cells recognize the recipient’s body as foreign and start attacking it. This problem can mainly happen in the following scenarios:

• After a bone marrow transplant (this is the most common situation)
• After transplanting solid organs that have a lot of lymphoid cells, like the liver
• After transfusing blood that hasn’t been exposed to radiation

Here’s what usually happens for GVHD to occur: First, immune cells need to be transferred from a healthy person to a person with a weak immune system. These transferred cells can then recognize antigens, a type of protein in the new body, as foreign.

Now, several factors can influence how likely you are to get GVHD and if you do get it, how severe it will be:

• Donor-host factors: If the transplant comes from an unmatched donor, if the human leukocyte antigen (HLA, a protein in our bodies) doesn’t match, or if the donor and recipient have different genders, GVHD is more likely.
• Stem-cell source factors: If the marrow (the spongy tissue inside our bones) has been frozen before being transfused or if umbilical cord blood is used, the chances of GVHD decrease.
• Immune modulation factors: Certain drug combinations can also lower the chances of GVHD. For example, combining cyclosporine, methotrexate and prednisone is more effective at preventing GVHD than just combining cyclosporine and methotrexate.

In research trials, statins, a type of medication, have been seen to reduce a particular type of cell that presents antigen, thus lowering the chances of GVHD. Lastly, chemotherapy and radiation therapy can cause local tissue damage and increase cytokine levels (proteins involved in cell signalling) in the blood. This could make your immune cells more likely to recognize host antigens as foreign and attack. Whole body radiation is associated with higher chances and severity of GVHD compared to chemotherapy alone.

Risk Factors and Frequency for Graft-Versus-Host Disease

Acute GVHD, a potential complication of stem cell transplantation from a sibling with a matched HLA, can affect up to half of these patients. This issue is even more common when the donors are not a match. Chronic GVHD, on the other hand, can happen anywhere from 6% to 80% of the time. GVHD is a major concern because it’s a leading cause of both sickness and death after stem cell transplantation, and over 10% of patients could die because of it.

There are certain factors that can increase the risk of developing acute GVHD after stem cell transplantation. These include:

• A higher degree of HLA mismatch.
• The occurrence of acute GVHD in the past.
• The sex of the donor and recipient.
• The age of the donor or recipient.
• If the recipient got stem cells from the peripheral.
• If the donor had alloimmunization.
• Positivity for cytomegalovirus and Epstein Barr virus.

Signs and Symptoms of Graft-Versus-Host Disease

Acute GVHD, or graft-versus-host disease, is a condition that commonly affects areas like the skin, gastrointestinal (GI) tract, and liver. In fact, these areas are impacted in around 70%, 74%, and 44% of cases, respectively. Other parts of the body that can be affected include the lungs, kidneys, eyes, and blood-forming system, and it can also reduce the body’s response to vaccines.

The main symptom for skin involvement is an itchy or painful rash that starts on the palms of the hands, soles of the feet, shoulders, and back of the neck. This rash can spread all over the body and merge together. In severe cases of GVHD, blister-like lesions mimicking toxic epidermal necrolysis (TEN), a serious skin disorder, can develop.

Main symptoms for GI involvement are diarrhea and stomach pain. Other symptoms can include inflammation and ulcers in the mouth, nausea, and vomiting. The diarrhea is a specific type that continues even when not eating and it can become bloody over time. This can result in the need for regular blood transfusions and make it hard to keep the body’s fluid levels balanced.

Liver involvement often appears together with either skin or GI symptoms and it rarely happens on its own. Signs of liver involvement include unusual results on liver function tests, typically showing high levels of bilirubin and alkaline phosphatase. Less common symptoms can include blood clotting disorders, high levels of ammonia in the blood, an enlarged liver, and light-colored urine and stool.

Chronic GVHD shares many features with disorders that affect connective tissues and systemic sclerosis. In the mouth, this condition may appear as a disease called lichen planus, which carries a risk of turning into oral squamous cell carcinoma. This form of cancer behaves more aggressively in patients who have had a stem cell transplant. Chronic GVHD can lead to frequent infections, often making immunosuppression treatment more complicated. If it involves the eyes, it usually affects the surface of the eye and can lead to dry eye or keratoconjunctivitis sicca. This signals a poor prognosis in GVHD.

Testing for Graft-Versus-Host Disease

Diagnosis of a particular condition usually takes place on the basis of symptoms and signs shown by patients. The same is true for a condition referred to as Graft Versus Host Disease (GVHD) that happens after a transplant procedure. There are three traditional factors that must be present for GVHD to occur.

The first factor is that immune cells present in the transplanted tissue (graft) must be functional and responsive. Second, the person receiving the transplant must have proteins that the transplant considers to be foreign, which can initiate an immune response. Finally, the person receiving the transplant should either be unable to effectively fight against the graft’s immune response or the graft must have enough time to develop an immune response.

All patients who undergo hematopoietic cell transplantation, a type of transplant involving blood-forming stem cells, are at risk of developing GVHD. This typically happens in the first few months after the transplantation. Skin and gastrointestinal (usually referring to rectal or the last part of the intestine) biopsies – procedures where small samples of tissue are removed for examination – can help confirm the diagnosis. How severe the disease is, or its stage, is determined by how spread out the symptoms are and the results of laboratory tests.

Researchers are looking into the use of biomarkers, substances in the body that can indicate the presence of a disease, for diagnosing GVHD and predicting its prognosis or outcome. However, none are currently ready to be used in clinical settings.

Treatment Options for Graft-Versus-Host Disease

Patients receiving hematopoietic cell transplantation, a therapy that infuses healthy blood-forming stem cells into the body, need to take specific preventative steps against a common side effect known as graft versus host disease (GVHD). Different treatment centers may follow slightly varying treatment plans, but generally these include a combination of medications like cyclosporine and methotrexate for several months after the transplant. Additionally, patients are normally given antibacterial, antiviral, and antifungal medicines to help prevent infections which they might be more susceptible to due to their weakened immune system.

Treating GVHD itself depends on how severe the symptoms are and what areas of the body are affected. The goal of treatment is to suppress the overactive donor T-cells (a type of white blood cell that can attack healthy cells in the body) but this has to be carefully done to balance reducing symptoms of GVHD without affecting the helpful graft versus tumor (GVT) response, where transplanted cells attack any remaining cancer cells.

The most commonly used treatment for GVHD is corticosteroids, a type of medication that reduces inflammation. For mild cases (Grade 1 GVHD), topical steroids applied directly to the skin are usually sufficient. If these don’t work, a medication called tacrolimus may be used. For more severe cases (Grade 2 or higher), systemic steroids, which circulate throughout the body, are needed. Methyprednisolone is commonly used. The treatment approach varies if GVHD involves the digestive tract. Nonabsorbable corticosteroids, such as budesonide or beclomethasone, may be given since these are more effective than systemic treatments. However, it’s important to note, if there’s a digestive tract infection, steroids should be avoided.

The dosage of corticosteroids is typically decreased gradually over several months to prevent the GVHD symptoms from suddenly worsening. Patients with chronic GVHD, a long-term form of the condition, may need to take steroids for 2-3 years or even for their whole lives. In severe cases, a medication called octreotide may be given to help manage diarrhea, a common symptom of GVHD.

There are other medication options, but their effectiveness is not yet clear. For treating chronic GVHD, cyclosporine can be added to the medication regimen to decrease steroid usage and duration. Often, it’s used with steroids for a more comprehensive immunosuppressive effect, helping to manage the disease while minimizing side effects.

What else can Graft-Versus-Host Disease be?

The conditions you might consider when diagnosing GVHD (a disease that can occur after an organ transplant) will depend on the symptoms you are experiencing. Here are a few possible conditions:

• Skin conditions: You could be dealing with medication side effects, viral rash, or skin damage from radiation therapy.
• Liver conditions: There could be an infection, especially one caused by a virus, drug-related liver damage, liver damage due to a sudden drop in blood flow (shock liver), side effects from immune-based therapies, blocked small veins in the liver, or liver cancer.
• Stomach and gut conditions:
• Diarrhea: This symptom could be a side effect of cancer treatment, immunosuppressant medications, antibiotics, or magnesium. It could also be due to infections (CMV, EBV, adenovirus, rotavirus, Clostridium difficile, Mycobacterium avium complex, Giardia, Cryptosporidium), abnormal blood clotting in tiny blood vessels (thrombotic microangiopathy), or impaired digestion of dietary fats (bile-salt malabsorption).
• Nausea, vomiting, and loss of appetite: These symptoms could be a side effect of cancer treatment, immunosuppressant drugs, radiation therapy, antibiotics, or opioids.

Healthcare professionals need to explore all these possible diagnoses to pinpoint the exact cause of your symptoms.

What to expect with Graft-Versus-Host Disease

The risk of death is generally higher when a person has moderate to severe GVHD (Graft Versus Host Disease) compared to mild disease. The disease is classified into different grades – for example, with grade C, only about 25% of people survive 5 years, and for the most severe grade (grade 4), the survival rate is only 5%.

How well someone responds to their first treatment has a big impact on their survival chances. There are several factors that can predict a worse outcome for people with either acute (short-term) or chronic (long-term) GVHD. These include widespread skin symptoms, diarrhea, low platelet count (thrombocytopenia), high liver enzymes (a sign of liver damage), and symptoms affecting the lungs or liver.

Spotting these signs early on, and treating them aggressively, is key to improving chances of survival and overall patient outcomes.

Possible Complications When Diagnosed with Graft-Versus-Host Disease

GVHD, which is a complication of a specific type of stem cell transplant, can lead to additional problems. These include various types of lung disease and a condition called pleuroparenchymal fibroelastosis. These extra complications can increase both sickness and death chances in those who receive transplants.

Additional complications include issues with the digestive system which can cause fibrosis (scarring), irregular movement of the digestive tract, and malabsorption (difficulty absorbing nutrients). Lung complications can further cause bronchiectasis (a permanent enlargement of parts of the airways of the lung). Infections are common and can sometimes be fatal. When it comes to the liver, complications include inflammation of the liver’s blood vessels, destruction of the bile duct, and inflammation around the bile duct. However, doctors do not regularly check for these complications through a liver biopsy due to associated low platelet count. Instead, they typically use liver function tests and imaging studies to check for liver complications in GVHD.

1. Lung complications:
• Various types of lung disease
• Pleuroparenchymal fibroelastosis
• Bronchiectasis
2. Digestive system complications:
• Fibrosis
• Irregular movement of the digestive tract
• Malabsorption
3. Liver complications:
• Inflammation of the liver’s blood vessels
• Destruction of the bile duct
• Inflammation around the bile duct
4. Infections

Preventing Graft-Versus-Host Disease

Patients can make their GVHD (Graft-versus-host disease, which is a complication that can occur after a stem cell or bone marrow transplant) easier to manage through proper treatment, preventive measures, and counseling. They can also take some extra steps at home like:

* Skincare: Patients should moisturize their skin regularly, use sunscreen with a high sun protection factor, avoid scratching stitched areas, and wear long clothes to keep their skin protected.
* Mouth care: Regular dental care with fluoride toothpastes or rinses is recommended.
* Diet: Patients should steer clear of foods that can cause diarrhea, like spicy foods. It’s important to be thoughtful about what they eat.
* Hygiene: It’s very important to avoid sources of infection. Patients should wear a mask over their face and nose when they go out and keep their hands and feet clean to lower their chances of catching an infection.

Also, patients and those who care for them should get their flu and pneumonia vaccines. This is really important because it can protect them from serious lung illnesses.