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Graft-versus-host disease

Acute graft-versus-host disease (GVHD) with subsequent complications from infection is the most significant cause for early death after an allogeneic stem cell transplantation. 

An allogeneic stem cell transplantation is carried out by transferring hematopoietic stem cells from an individual who is usually tissue-identical, but genetically different from the patient. Due to genetic differences outside the HLA system, immunological responses occur between the donor cells and the recipient or graft-versus-host reactions, which eventually cause graft-versus-host disease. The cause of the GVH reaction and disease is due to the T-lymphocytes of the donor attacking cells and tissue in the recipient where the immune system is compromised from high doses of chemotherapy, possibly combined with radiation and immunosuppressive medication.  

GVHD can be life-threatening, but experience has shown that leukemia patients with GVHD have a lesser chance of recurrence of leukemia. This is well studied in patients treated with allogeneic stem cell transplantations for chronic myeloid leukemia. 

If the transplanted marrow or stem cells from blood is filtered for T cells, fewer patients develop GVHD, but the risk for recurrence is significant. It appears that T cells from the donor have an anti-leukemic affect, GVL (graft-versus-leukemia). Additional evidence that alloreactivity has an antileukemic effect is that patients with leukemia-transplanted stem cells from an identical twin, have a greater chance of recurrence than patients with stem cells which are not genetically identical.  

Acute graft-versus-host disease 

Acute GVHD gives rise to symptoms especially in the skin, liver, and/or stomach/intestines. There will often be differential diagnostic problems since all clinical signs can be observed for conditions other than GVHD. If possible, the diagnosis should be verified histologically.

Acute GVHD usually occurs by day 100 after the transplantation with myeloablative conditioning. For reduced conditioning, acute GVHD is often observed later on. 

Grading

  • Grade 1: Mild, the patient usually does not require treatment.
  • Grade 2–3: The patient requires treatment.
  • Grade 4: Life-threatening situation for the patient.

Symptoms of acute GVHD

Skin

Exanthema which varies in appearance. Before day 21, a skin biopsy is not appropriate as it will be difficult to interpret. If the platelet count is over 30 x 109/l after a platelet infusion, a biopsy should be considered. The patient must observe their skin daily for rash and quickly report to their doctor if there are any changes. It is important the patient keeps their skin moist with thick cream.

Clinical example: 

  • Hand
  • Foot
  • Upper body 

Liver

Each form of liver disfunction with elevated bilirubin may be due to GVHD. In addition to hepatitis A, B, C, non A, non B, non C and CMV infections, such biochemical disturbances may have a series of other causes for example medications, VOD (veno-occlusive disease) and microangiopathy. A liver biopsy should be considered if a platelet count of over 50 x 109/l can be ensured, possibly after a platelet transfusion.

Before the biopsy is taken, an ultrasound exam should be performed to look for focal lesions which may be due to infection. The biopsy can be guided by ultrasound. In addition to a normal histological examination, the biopsy should be examined for microorganisms (fungus, acid-resistance rods, virus).

If the liver is attacked by GVHD, this will be detected by the blood tests. The patient often does not notice any symptoms but may be jaundiced.

Stomach/bowel

In principle, the entire gastrointestinal tract may be affected. That is, the patient may develop mouth sores, dysphagia, nausea, diarrhea, and abdominal pain. Ileus, bleeding, an malabsorption also occur. Therefore, a differential diagnosis may be difficult because of possible the side effects from conditioning and infections (fungus, virus, antibiotic associated colitis, ulcer, gastritis).

It is very important that the doctor is notified if the patient has diarrhea, even if it may be due to other conditions.  

An endoscopic examination should be considered with a biopsy if adequate hemostasis can be ensured, and the biopsy is crucial for the choice of treatment. Biopsies taken during the 21-28th day are difficult to interpret.

Prophylaxis

To prevent serious of life-threatening GVHD, the patient receives ciclosporin A daily from the day before the transplant and for 9-12 months after. The patient also receives 4 infusions of low-dose methotrexate during the first 11 days after the transplant. Other immunosuppressive regimens are used as well. The most important risk factors for acute GVHD are HLA incompatibility and the age of the patient. When a complete HLA-compatible sibling donor is used, the risk for such serious GVHD is above 30% with a prophylactic regimen and treatment with gluticosteroids is necessary. With the use of unrelated donors, the risk is about double.  

Treatment of acute GVHD

Treatment of acute GVHD, in the first round, is additional immunosuppression with intravenous gluticosteroids. To begin with, a relatively high dose of methylprednisolone is administered 2 mg/kg/day. Later dosing and transition to oral administration depends on the response. For lacking or poor response to glucocorticoids, it is appropriate to treat with anti-thymocyte globulin (ATG), monoclonal antibodies against T-cells, TNFą-inhibitors or other immunosuppressors. Use of these types of medications increases the risk for infection.

Chronic graft-versus-host disease

Chronic GVHD (GVHD after day 100) can affect more organs than acute GVHD usually does, and the condition can sometimes cause long-term and problematic symptoms.

The conditions will usually "burn out" but may require treatment in periods and sometimes for multiple years.

The most important complication for GVHD is infection, which may bave a dramatic and sometimes fatal outcome if the proper treatment is not started early enough, but also when the correct treatment is given.

Diagnosis and treatment of chronic GVHD requires a close dialog between the transplant division and health clinic where the patient lives.

A limited disease is characterized by the following conditions: 

  • localized skin affection
  • liver dysfunction caused by chronic GVHD

An extensive disease is characterized by one or more of the following conditions:

  • general skin affection 
  • localized skin affection and/or liver function disturbances caused by chronic GVHD
  • liver histology—chronic aggressive hepatitis, "bridging" necrosis or cirrhosis
  • eye affection
  • affection of small salivary glands or oral mucosa detected in lip biopsy
  • affection of other target organs

Symptoms of chronic GVHD

Skin

May resemble progressive or systemic sclerosis. Dispigmentation, lupoid rash, lichenoid rash, scar changes, dry/scaly skin.

Hair growth

GVHD in the hair follicles may lead to thinner hair growth than previously. This applies to the entire body. Some patients will never grow their hair back.

Eyes

The patient may have dryness and soreness in their eyes.

Mucosa

Mucosa may be dry and stiff.

Genital mucosa:

  • Women—May have problems with vaginal dryness and soreness. There may be changes, sores, and some may have problems with adhesions. It is important that women receive follow-up care by a gynecologist regularly after a transplant. It is also important that the patient speaks to their doctor/nurse about any changes.

  • Men—Adherences may occur on the foreskin. It is important the patient speaks to their doctor/nurse if such problems occur. 

Intestines

Esophagitis with dysphagia, reflux gastritis with dyspepsia, nausea, anorexia, malabsorption, weight loss.

Liver

Chronic GVHD in the liver appears as elevated transaminase, increase in bilirubin, jaundice, and itchy skin. 

Neuromuscular

Muscle stiffness, asthenia, myastenia, contractures, and at rare times myositis.

Peripheral blood

Pancytopenia, thrombopenia, leukopenia, anemia

Lungs

Causes asthma and bronchitis-like symptoms and may cause reduced lung capacity. The patient is often more susceptible to lung infections.

Infections

Encapsulated bacteria. Viruses such as varicella zoster, CMV. Some patients develop hypogammaglobulinemia.

 

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