What is Graft-versus-Host-Disease ?


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Introduction
T-Cells
Graft-versus-Host-Disease
Stages of acute GVHD
Acute GVHD
Prevention & treatment of acute GVHD
T-Cell depletion
Chronic GVHD
Treatment of chronic GVHD
Long term concerns
Coping with the stress of GVHD
Symptoms & side effects of chronic GVHD
Susan Mitchell

 

 

Introduction


  Graft-versus-host disease is a frequent complication of allogeneic BMTs. In GVHD, the donor's bone marrow attacks the patient's organs and tissues, impairing their ability to function, and increasing the patient's susceptibility to infection.

  Approximately 50 percent of patients undergoing an allogeneic BMT with a related HLA-matched donor develop GVHD. Fortunately, the majority of cases are mild. GVHD is not a complication of autologous BMTs.

  GVHD is often discussed as if it were a single disease. It is, in fact, two diseases: acute GVHD and chronic GVHD. Patients may develop one, both or neither. Acute and chronic GVHD differ in their symptoms, clinical signs and time of onset. (Clinical signs are the results of physical exams, x-rays or lab tests that confirm the existence and extent of a disease.)

  GVHD can be a temporary inconvenience or a serious, life-threatening disease. Older BMT potients are more likely to develop GVHD thon younger patients. The incidence and severity of GVHD is also higher among patients whose bone marrow donor is unrelated or not perfectly matched.

  The symptoms of GVHD are many and varied, and the list may at first be overwhelming. Keep in mind however that most patients undergoing an allogeneic BMT with a related HLA-matched donor develop only a mild or moderate case of GVHD, or no GVHD at all. Although GVHD can be life- threatening or fatal, most patients survive the disease without long-term disabling side effects.

 


T-Cells

   T-cells are special white blood cells that recognize foreign matter in the body. T-cells orchestrate attacks on bacteria, viruses and other substances foreign to the body. They can also distinguish "self" from "non-self"-human cells that belong in one person's body and those that do not.

  On the surface of many human cells is an inherited set of genetic markers called "human leukocyte antigens" (HLA). Like a fingerprint, no two persons' set of HLA markers are exactly alike (except for identical twins). The T- cells use these HLA markers to distinguish "self" from "non-self." If a "non- self" human cell is encountered in the body, the T- cells quickly activate the immune system to destroy it. The greater the disparity between the body's HLA markers or "tissue type" and that of the foreign human cell, the swifter and more vigorous the attack. (Click here)for more on the HLA system).

  The ability of the immune system's T-cells to distinguish "self" from "non- self" can create a serious problem after allogeneic BMTs. Unless the donor is an identical twin, his or her tissue type (those HLA markers or genetic fingerprints) will differ from that of the patient. The patient's T-cells may identify the donor's bone marrow as "non-self" and attack the donated bone marrow. This is called graft rejection.

  To prevent graft rejection, total body irradiation (TBI) and/or drugs such as cyclophosphamide are used to kill the cancerous cells and to suppress a patient's immune system. The radiation and drugs disrupt the ability of T- cells to recognize the donated bone marrow as "non- self" and to launch an immune system attack. Immune system suppression is not required in autologous BMTs since the bone marrow transfused into the patient is his or her own.)

 


Graft-versus-Host-Disease


   The donor's marrow also contains T-cells. When transplanted into the patient, the donor's T-cells may look at the HLA markers on the patient's cells, identify the cells as "non-self" and unleash an attack on the patient's tissues and organs. Because the patient's own immune system is suppressed prior to the transplant, it cannot launch a counterattack. This condition is called graft-versus-host disease (GVHD). The "graft" is the donated bone marrow and the "host" is the BMT patient or bone marrow recipient.

 


Stages of acute GVHD


 Stage 1 (mild) : a skin rash over less than 25% of the body.

Stage 2 (moderate) : a skin rash over a more than 25% of the body accompanied by mild liver or stomach and intestinal disorders.

Stage 3 (severe) : redness of the skin, similar to a severe sunburn, and moderate liver, stomach and intestinal problems.

Stage 4 (life-threatening) : blistering, peeling skin, and severe liver, stomach, and intestinal problems.



Acute GVHD



   Acute GVHD usually occurs during the first three months following an allogeneic BMT. T-cells present in the donor's bone marrow at the time of transplant identify the BMT patient as "non-self' and attack the patient's skin, liver, stomach, and/or intestines.

  The earliest sign of acute GVHD is often a skin rash that usually first appears on the patient's hands and feet. The rash may spread to other parts of the body and develop into a general redness similar to a sunburn, with peeling or blistering skin. Cramping, nausea, and watery or bloody diarrhea are signs of GVHD in the stomach or intestines. 9aundice (yellowing of the skin and eyes) indicates that acute GVHD has affected the liver.

  Physicians grade the severity of acute GVHD according to the number of organs involved and the degree to which they're affected. Acute GVHD may be mild, moderate, severe or life-threatening (see box).

  To minimize the risk of graft rejection and GVHD, allogeneic BMT patients are given drugs to prevent GVHD before and after transplant that suppress the immune system. Use of these drugs, however, increases the risk of infection. Precautions taken to limit the patient's exposure to harmful bacteria, viruses and fungi during this period may include special air-filtering equipment in the patient's room, frequent hand- washing by visitors, use of masks, gloves and robes by the patient and/or visitors, and elimination of fresh fruits, flowers and vegetables from the patient's environment which may harbor potentially harmful bacteria.

  Patients over the age of 30 are more likely to develop acute GVHD than younger patients. Patients receiving marrow from a female donor who has had two or more viable pregnancies also are more likely to develop acute GVHD.


Prevention & Treatment of Acute GVHD

 

   Although GVHD is not yet preventable, steps can be taken to reduce the incidence and severity of GVHD.

  Administration of immunosuppressive drugs such as cydosporine (alone or in combination with steroids) and methotrexate prior to the transplant have proven effective in reducing the incidence and severity of GVHD. They may be administered for several months post-transplant, particularly if acute GVHD progresses to Stage II, or if the patient develops chronic GVHD.

  Cyclosporine, steroids and methotrexate weaken the ability of the donor's T cells to launch an attack against the patient's organs and tissues. These drugs, however, have potential side effects. Cyclosporine can be very toxic to the kidneys, cause increased hair growth on the body, especially facial hair on women, and on rare occasions can result in neurological problems such as seizures, confusion, anxiety, and changes in thought processes. Methotrexate may cause inflammation of the mouth, nose and/or throat. Side effects of steroids indude weight gain, fluid retention, elevated blood sugar level, mood swings and/or confused thinking. These side effects are temporary and disappear once use of these drugs is discontinued.




T-Cell Depletion

 

   Another technique sometimes used to reduce the severity and incidence of acute GVHD is called "T-cell depletion." Since T-cells identify foreign antigens, researchers hypothesized that removing T-cells from the donor's marrow would decrease the incidence and severity of GVHD. And so it did, reducing the incidence of acute GVHD in leukemic patients from approximately 50 percent to less than 15 percent.

  Unfortunately, donor T-cells also appear to play a role in the successful engraftment of the bone marrow in the patient. Thus, while T-cell depletion has decreased the incidence of GVHD in leukemic patients dramatically, the incidence of graft-rejection has risen from near zero in patients whose marrow is not T-cell depleted to 10-30 percent in patients receiving T-cell depleted marrow, resulting in no improvement in long-term survival rates.

  In addition, a mild or moderate case of chronic GVHD seems to confer an anti- leukemic effect on the patient. Thus, a little bit of GVHD in leukemic patients may actually be desirable. Completely depleting donor bone marrow of T-cells has not only reduced the incidence of GVHD, but has resulted in relapse rates as high as 65 percent among certain subsets of leukemic patients studied.

  BMT centers have tackled this dilemma in several ways. At some centers, less than 100 percent of the T-cells are depleted from the donor's bone marrow prior to infusion. This techniques appears to reduce the incidence of graft- rejection normally associated with complete T-cell depletion, and preserves some of the graft-versus-leukemia effect a mild case of GVHD confers.

  Another T-cell depletion technique now under study looks promising. In a trial involving 45 CML (chronic myelogenous leukemia) patients transplanted with marrow from an HLA-matching sibling, the T-cell called CD-8 was selectively purged from the donor's marrow. Using this technique, the incidence of acute GVHD was reduced to 20 percent (from 50 percent when unpurged bone marrow marrow is used), and the high rate of relapse experienced among leukemic patients who receive marrow completely purged of all T-cells did not occur. Graft-rejection was 10 percent, as compared to 10- 30 percent when all T-cells are depleted from bone marrow.



Chronic GVHD



   Chronic GVHD usually develops after the third month post-transplant. Scientists believe that new T-cells produced after the donor's bone marrow has engrafted in the patient may cause chronic GVHD.

  Most patients with chronic GVHD experience skin problems that may include a dry itching rash, a change in skin color, and tautness or tightening of the skin. Partial hair loss or premature graying may also occur.

  Liver abnormalities are seen in many patients with chronic GVHD. This is usually evidenced by jaundice and abnormal liver test results.

  Chronic GVHD can also attack glands in the body that secrete mucous, saliva or other lubricants. Patients with chronic GVHD usually experience dryness or stinging in their eyes because the glands that secrete tears are impaired.

  Glands that secrete saliva in the mouth are often affected by chronic GVHD and, less often, those that lubricate the esophagus, making swallowing and eating difficult. It's common for patients with chronic GVHD to experience a burning sensation in their mouths when using toothpaste or eating acidic foods. Good oral hygiene is imperative to minimize the risk of infection.

  Chronic GVHD may attack glands that lubricate the stomach lining and intestines, interfering with the body's ability to properly absorb nutrients. Symptoms include heartburn, stomach pain and/or weight loss.

  Occasionally patients with chronic GVHD experience "contractures," a tightening of the tendons in pints that makes extending or contracting their arms and legs difficult. Chronic GVHD can also affect the lungs, causing wheezing, bronchitis, or pneumonia.

  As is the case with acute GVHD, older patients are more likely to develop chronic GVHD than younger patients. Seventy to 80 percent of patients who develop chronic GVHD will previously have had acute GVHD. Chronic GVHD is also more common in patients whose donor is unrelated or whose marrow is not perfectly matched.

 


Treatment of Chronic GVHD


   Chronic GVHD is usually treatable with steroids such as prednisone, ozothioprine and cyclosporine, which suppress the patient's immune system. Antibiotics such as Bactrim or penicillin or both are usually taken to reduce the risk of infection while chronic GVHD is being treated. In addition, patients may be required to wear face masks while around other people, stay out of crowds, and avoid fresh plants, fruits and vegetables. Patients with chronic GVHD are usually advised to avoid vaccinations with live viruses such as German measles, tetanus, polio, etc. until the GVHD problem is completely resolved and use of immunosuppressive drugs ends.

  Researchers have been studying the effectiveness of using other drugs to control chronic GVHD in patients resistant to standard therapy. A recent study found thalidomide to be effective in controlling chronic GVHD in "high risk" patients (i.e., those likely to develop life-threatening GVHD) with minimal side effects (drowsiness).



Long Term Concerns


   Although most patients recover from GVHD, some symptoms may persist even after the disease has been completely resolved. Patients who 've had GVHD usually experience long-term skin sensitivity and must avoid prolonged exposure to sunlight, using strong sunblockers on any exposed skin. Scarring of the skin may also occur.

  Eye irritation sometimes persists long-term, and is usually managed with eye drops. Chronic diarrhea and failure of the stomach to properly absorb nutrients may also continue after all clinical signs of GVHD disappear. Some patients experience persistent liver problems and, less frequently, lung
problems or contractures.

  While GVHD can be a very unpleasant and sometimes fatal complication of an allogeneic BMT, most patients survive the experience without disabling long- term side effects. Scientists are continuing to investigate new ways to prevent and better manage GVHD in the future.



Coping with the stress of GVHD


   Since many patients undergoing an allogeneic BMT experience some degree of GVHD, physicians typically discuss GVHD with patients in detail prior to their transplant. Many patients find this discussion overwhelming and frightening, particularly if the risks of GVHD are not put into some perspective. Patients often do not understand that a case of GVHD can be mild, moderate or severe, and that death, disfigurement or permanent disability is not the usual outcome.

  A diagnosis of GVHD will affect most patients' emotional and psychological health. Weary of the many complications associated with a BMT, patients often view GVHD as yet another setback that will delay their recovery, and become angry or depressed.



Symptoms, side effects
of chronic GVHD

MOST COMMON


o rash, itching, general redness of skin
o dark spots, tautness of skin
o jaundice (yellowing of skin and eyes)
o abnormal liver tests
o dry, burning eyes
o dryness or sores in mouth
o burning sensation when eating acidic foods
o bacterial infections

 LESS COMMON


o skin scarring
o partial hair loss, premature graying
o severe liver disease
o vision impairment
o heartburn, stomach pain
o difficulty swallowing
o weight loss
o contractures
o difficulty breathing
o bronchitus, pneumonia


   The side effects of drugs used to treat GVHD can further stress a patient's already delicate emotional state. Depression, confusion, anxiety, roller coaster-like mood swings, and exaggerated feelings (anger, excitement, sadness, etc.) disproportionate to the situation are common and can make the GVHD recovery period extremely trying for patients and their loved ones. Keeping in mind that these side effects are tempo- rary can help everyone involved-patient, family and friends-better cope with this period of treatment. In rare instances, medications may be prescribed to stabilize mood swings and reduce anxiety.

  Many patients find that building a support system during the recovery period enables them to better cope with the stress of GVHD and other post-transplant complications. This can be done in several ways.

  Some patients expand the network of friends and relatives upon whom they rely for help. This can benefit not only the patient, but can give respite to the primary caregivers as well. Family and friends are often eager to help but don't know what to do. Many would be happy to be included on the list of people the patient can call when an understanding, listening ear is needed.

  Other patients find support groups organized through their hospital, the American Cancer Society, or similar organizations helpful. Talking with someone who has been through the same experience can lend a unique type of support to patients during this difficult period. Some hospitals and religious organizations also make available one-on-one support services for patients recovering from serious illness. Transplant physicians can usually recommend a social worker who can link patients with various support groups and services.

  Often patients find that a professional therapist is very helpful. A therapist can provide a safe environment for the patient to express his or her anger and frustrations, and may have creative suggestions to help a patient cope with his or her stress. Transplant physicians can usually refer patients to therapists experienced in dealing with the complications of BMTs.

  Most patients undergoing GVHD treatment experience temporary changes in appearance as a result of the disease or medications used to treat GVHD. Excessive weight gain, a bloated or "moon" face, jaundice (yellow eyes and skin), excessive hair growth on the body, particularly the face and back, and skin irritation which may have the appearance of a mild to severe sunburn can all diminish a patient's self-esteem.

  Patients cope with changes in appearance in different ways. Some find it helpful to keep pictures of themselves taken before their illness on hand as a reminder that the physical changes are temporary. Others prefer to avoid reminders of their changed physical appearance al together.

  Because the immune system is suppressed during GVHD recovery, a patient's ability to socialize and interact with the public is limited. Face masks may be required when venturing out of the home and special care must be taken to avoid crowds, people who are ill or those who've been exposed to illness.

  Patients do not, however, need to feel like a prisoner in their own home. Seeing movies during daytime hours when attendance is low, shopping in stores during off-hours, eating in restaurants at 5 p.m. instead of the more crowded 7-8 p.m. dinner hour, etc. allow patients to continue to enjoy public activities during their recovery period without unduly increasing their risk of infection.

  Battling GVHD can be a difficult and frustrating experience. For most patients, however, the battle will be temporary and successful.


Susan Mitchell



   Susan Mitchell, a BMT patient with aplastic anemia, sums up her experience with GVHD this way: "Sometimes, as I fought off repeated infections and looked at myself in the mirror I thought there would be no end to my misery. But today I'm realizing a happy ending to all of this. Every day is a little brighter and better. My GVHD is gone, my liver is returning to normal, my skin color is back, and I don't itch anymore. I don't do 10 km runs yet, but walking seems to suit me well for the time being.

  I haven't returned to work yet, but I find my volunteer work at the local hospital and the Heart of America (a bone marrow registry) very rewarding. I take life one day at a time and thank God for giving me loving and supportive family and friends. I never gave up on life and kept a positive attitude. I hope anyone who's facing a BMT finds the same strength I did and never gives up."


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