Graft-Versus-Host Disease is one of several complications that can occur post-transplant, but the most desired complication to avoid. The reverse, Host-Versus-Graft Disease may also occur; in Leukemia patients, GVHD can be beneficial in producing Graft-Versus-Leukemia Disease, often referred to as the Leukemia Effect, but such is not the case in patients with Aplastic Anemia.
GVHD & HVGD
Graft-Versus-Host Disease is the process of the grafted cells attacking the host cells, usually beginning with the skin, and in more severe cases, attacking other internal organs. HVGD is the process of the host immune system attacking the transplant cells (or organ). Graft-Versus-Leukemia effect is the process during which the grafted cells attack the leukemia cells.
GVHD for Aplastic Anemia transplant survivors is a serious complication. It most commonly begins with a mild case of skin GVHD, which even with treatment can progress to GVHD of the GI-tract and other internal organs. In most cases, skin GVHD is highly treatable. GVHD of the skin can be treated with steroids, photopheresis, and other methods. It is the unattended progression of GVHD that is far more serious; hence, it is critical to attend all clinic appointments.
The medical community almost always refers to Graft-versus-Host Disease by its acronym, GVH, as do most people who are privy to medical treatments involving the disease.
So what is GVHD?
Basically, GVHD occurs when cells realize they are in the wrong body, and launch an immune system attack.
classification of GVHD
Previously, GVHD was separated into Acute and Chronic forms according to when the disease began. The disease was Acute if it occurred within the first 100 days, and Chronic if it occurred after the first 100 days.
The National Institutes of Health (NIH) proposed to recognize two categories of GVHD (See Blood Journal, Hematology Library, Fred Hutchinson, Cancer Research Center, Seattle, Washington):
Pursuant to the NIH's proposal, clinicians classify GVHD into Acute or Chronic forms by its symptoms, that is, the amount of damage it has caused to the liver, skin and mucosa, and the gastrointestinal tract (GI-tract), as well as its timing. (Mucosa refers to the mucus membranes that trap pathogens in the body to prevent further disease; they are found in the skin, nostrils, lips, ears, genital area, anus, penis and foreskin, clitoral hood and throughout the internal respiratory system).
Treatment of Acute & Chronic GVHD
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Classification is important, because treatments differ.
GVHD grading ranges from a low Grade I (one) to a high Grade IV (four) based on its involvement of the skin, liver and gut.
"Acute" means that the disease is quickly onset. Acute GVHD targets the skin, liver and intestinal tract; it can also target other organs and the mucosa. Acute GVHD can cause damage to the immune system, bone marrow, thymus, and lungs, as well as cause pneumonia.
Where previous definitions of Acute GVHD restricted its diagnosis to the first 100 days post-transplant, reports by the Cancer Center in Seattle, Washington of observations of patient symptoms have shown that acute GVHD can present several months post-transplant.
"Chronic" means that a disease develops over time. Those reports discussed above by the Cancer Center of Seattle, Washington also denote that chronic GVHD can present as early as 50 60 days post-transplant.
Chronic GVHD also causes selective damage as noted above for Acute GVHD, but chronic GVHD also damages the connective tissues (structural, support and middle skin tissues) and exocrine glands (sweat glands, salivary glands, stomach, liver, pancreas).
causes of GVHD
T-cells or T lymphocytes are a particular type of white blood cell matured by the thymus (the T in T cell represents its manager, the thymus). There are several types of T cells in the body, such as T helper cells, Memory T cells responsible for remembering past infections, Regulatory T cells or Suppressor cells, and the one that is perhaps of most interest to patients inflicted with GVHD, Cytotoxic T cells that play a role in transplant rejection.
Graft-Versus-Host Disease most often results from mismatched HLA donors, meaning patients who received a transplant from a person whose DNA didn't closely match the patient's. HLA typing is a procedure for matching potential donors to people needing transplants; it identifies and matches proteins on the cell surface.
GVHD can also occur in transplant patients who were closely matched to their donor, referred to as having a closely matched or perfectly matched HLA typing. Even in perfectly HLA-matched transplants there are still genetically differing proteins on the cells. In transplants involving donations from a first-degree relative, the recipient's immune system is unable to destroy the donor lymphocytes, which results in GVHD.
Notably, transplanted t-cells are undesirable because they can effect GVHD, but they are valuable for engraftment because they prevent the recipient's remaining immune system from rejecting the graft (Host-versus-Graft Disease).
Although less frequent, GVHD can occur from a blood transfusion, referred to as TA-GvHD. The donor's T lymphocyte cells recognize that they are in a foreign body, and mount an immune response attacking the recipient's immune system. Because the recipient is immunosuppressed by drugs, their system is unable to destroy the donor cells. The result is GVHD. TA-GvHD is far less frequent (.1-1.0%), but its mortality rate (80-90%) is much higher than GVHD, most frequently involving direct attacks on the bone marrow, hemorrhages, pancytopenia and liver dysfunction. Blood irradiation is used to prevent TA-GvHD by destroying the lymophcytes.
symptoms of GVHD
Often times, the first symptom of GVHD is a loss of appetite, which may be experienced in conjunction with nauseousness and vomiting. Within a short period of time, a rash will typically develop on the skin. GVHD rash appears lacy and clustered, and spreads quickly from the abdomen and back, neck and arms to legs. Medical journals report that a rash will first develop on the palms of the hands and souls of the feet, but those rashes may be undetectable.
Upon recognizing a GVHD rash, a patient should immediately contact their transplant team. Lotions should be applied as soon as possible to prevent drying, chapping, bleeding and other complications from erupting on the skin surface. Any open wounds should be covered until they scab to prevent bacterial, fungal or viral infection. All this is "a good idea" and should always be run by your doctor.
Skin GVHD frequently presents with an elevated liver enzyme level, but not always.
Frequently, a drop in both red and white blood cells will subsequently follow, but not always.
Skin GVHD first appears as a bad sunburn, then darkens like a suntan, except with a heavy rash. The rash can be localized or affect derma across the entire body, but is often most severe in the torso area (stomach, back, thighs), but can spread over the entire body. The degree to which the rash exists and the time in which it spreads are indicative of the level of GVHD involved.
Advanced skin GVHD can blister and peel.
GVHD often goes beyond the skin affecting the entire GI tract from inside the mouth to the colon, and other internal organs. The liver is often one of the first organs attacked during an onset of GVHD.
Treatment of GVHD
Once again, at this juncture, it cannot be stressed enough that anyone with GVHD should immediately contact their transplant doctor or medical team, and follow instructions verbatim. GVHD can quickly move from GVHD I to GVHD IV if not treated correctly and promptly.
Treatment of GVHD involves suppression of the immune system. Medications and treatment of GVHD is mandatory for survival.
Amongst the most common immunsuppressant drugs is Tacrolimus, and other corticosteroids, in addition to Photopheresis for skin GVHD. In many cases, steroids will treat and eliminate GVHD.
The body becomes quickly dependant upon the steroids, therefore the withdrawal from steroids is a long process of stepping down the dosages. Steroids also cause pain, sometimes to a great degree, particularly when the dosage is reduced. Other side effects include increased risk of infection. Doctors seek to help minimize complications from GVHD treatments.
Steroid creams are also prescribed for application to the affected areas. It is highly recommended that anyone who is prescribed a steroid cream use it consistently. Studies indicate that the regular use of steroid creams results in elimination of the rash in the near future, and results in elimination of all signs of skin GVH in the long term (study recorded no signs at 4-year mark).
Dry mouth, dry eyes, and other dry tissue effects can result, and usually do appear. Cavities and tooth loss can occur because of the dry mouth. You may want to use dexamethasone is often prescribed, and works well to help symptoms of the mouth. Nystatin is for fungal infections of the mouth, but due to its numbing properties, patients may like to use it with the dex. One of the best over-the-counter products to try is Biotene.
Biotene makes a mouth rinse, which is great for use during the pre-transplant treatment in the hospital, or for anyone undergoing chemotherapy. Biotene gum is a great way to treat the mouth continuously. Biotene has coupons online: http://www.biotene.com/save-now.
How long is GVHD Medication Treatment Necessary?
Treatment of GVHD by medications is necessary until the donor cells stop attacking. This is referred to tolerance. Tolerance is a milestone date for transplant patients who have had Chronic GVHD. On average, treatment for Chronic GVH last from two to three years from the initial diagnosis of Chronic GVHD. In some cases (about 20%), patients require treatment for as long as 7 years.
When steroids alone fail to treat the GVHD, it may be possible that the patient has become refractory. In that instance, steroids will not treat the GVHD regardless of the dosage or length of treatment.
Secondary Treatments for GVHD
If steroids fail, the next step is determine if the steroids should be continued and what secondary treatment should be started. According to the Blood Journal article cited above, steroid treatments are often continued despite their side effects in patients with prominent intestinal manifestation of GVHD.
Secondary treatments include antibodies, polyclonal or monoclonal, and Antithymocyte Globulin (ATG). ATG is an immunosuppressant drug.
Immunosuppressant drugs are prescribed for transplant patients to prevent the immune system from attacking the transplanted cells. Patients begin taking immunosuppressant drugs very early in the transplant process, and continue to take these life-sustaining drugs for quite some time.
Immunsuppressant drugs do as their name suggests; they suppress the immune system. What exactly does that mean? Immunosuppressant drugs hinder the ability of certain T-cells, thus preventing them from launching an immune attack. Unfortunately, the further the immune system is suppressed, the greater the risk is for viral, bacterial and fungal infections.
It is critical for people with suppressed immune systems to avoid coming into contact with people that have any type of infection (bacteria, viral or fungal), any type of contagious disease or disorder, or who have received any type of live virus vaccine. If you have questions, ask your doctor right away. Infections are nothing to relax about - prompt, immediate and effective treatment is mandatory for long term survival.
If the skin becomes leathery and inelastic due to GVHD, treatment might then include Photopheresis.
GVHD complications can occur, and when they do, they can be difficult to treat. GVHD of the GI tract can result in the patient being unable to consume food and liquids, or unable to retain nutrition resulting in IV feedings. Further progression of the disease can be fatal.
GVHD can attack internal organs resulting in irreversible long-term effects and even life-threatening complications.
GVHD is a complex disease that can involve many organs, tissues and cells. There is no one prognosis for all of the complications that GVHD can pose. Generally speaking, a person with Stage 1 GVHD has a very good prognosis provided that medical treatment is sought right away, and all courses of treatment recommended are fulfilled.
A person with Stage 4 GVHD has a poorer prognosis. Additionally, it is not just the GVHD that is problematic. A person with GVHD will be immunosuppressed to stop the GVHD from progressing. Immunosuppression always presents opportunities for further infections, some of which can become severe and pose other severe complications or cause death.
is there any good news about GVHD?
Unlike Leukemia, GVHD is not beneficial for Aplastic Anemia patients. If it develops, and the doctors are made aware of it quickly, it is often very treatable with no long term effects. While a doctor would need to be consulted about this next statement, it may help to know that most effects of lower level GVHD are reversible, such as the high liver enzymes and any effects upon the liver, as the liver is one of the most forgiving organs (and quick to heal itself).
Notably, transplanted t-cells are undesirable because they can cause GVHD, but they are valuable for engraftment because they prevent the recipient's remaining immune system from rejecting the graft (Host-versus-Graft Disease). In that regard, some AA specialists within the medical community believe that some GVHD can be a good thing.
Pediatric lung transplantation for GVHD following BMT.
Blood Journal, 2006.
Patient & Caregiver Resource Manual For Adult Allogeneic Patients, Seattle Cancer Care Alliance, Long-Term Follow-Up Program, Dr. Fred Hutchinson