Chronic GVHD Issues

Graft-versus-host disease (GVHD) is a term used to describe a battle between the transplanted stem cells and the patient’s body. This is a complication that occurs when the new stem cells (the graft) reject or see your body (the host) as foreign and attack the tissues and organs.

Immune cells recognize other cells that are not genetically identical. The graft versus host reaction results when the donor’s immune cells, especially the T lymphocytes, sense that the host cells are different from themselves. In the case of stem cell transplantation, the donor cells monitor the recipient’s cells for differences and attack them if they find significant variations. The differences may involve cell surface proteins that are not measured by HLA typing, or there may be subtle differences in HLA type that permit transplantation but cause the reaction. With the exception of identical twins, some incompatibility will exist even though HLA testing indicates enough similarity to permit a successful transplant.

While donor T-Cells are undesirable as effector cells of graft-versus-host-disease, they are valuable for engraftment by preventing the recipient’s residual immune system from rejecting the bone marrow graft (host-versus-graft). In addition, as bone marrow transplantation is frequently used to treat cancer, mainly leukemias, donor T-cells have proven to have a valuable graft-versus-tumor effect. A great deal of current research on allogeneic (donor) stem cell/bone marrow transplantation involves attempts to separate the undesirable graft-vs-host-disease aspects of T-cell physiology from the desirable graft-versus-tumor effect.

There are two phases of graft-versus-host-disease. Acute GVHD occurs within the first 3 months post transplant, and Chronic GVHD occurs anytime after 3 months (100 days) post transplant and can last a few months, a few years, to a lifetime. Both share similarities in terms of symptoms and varying severity, and the treatments are also almost identical in terms of drugs used. Both have the potential to be fatal however most cases are mild to moderate, can be managed with drugs and will resolve over time once the patient is weaned off the meds.

In the classical sense, acute GVHD is characterized by selective damage to the liver, skin (rash), mucosa, and the gastrointestinal tract. Newer research indicates that other GVHD target organs include the immune system (the hematopoietic system, e.g., the bone marrow and the thymus) itself, and the lungs in the form of idiopathic pneumonitis. Chronic GVHD also attacks the above organs, but over its long-term course can also cause damage to the connective tissue and exocrine glands.

Acute GVHD usually occurs during the first three months following an allogeneic SCT/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 (severe cases). Cramping, nausea, and watery or bloody diarrhea are signs of GVHD in the stomach or intestines. Jaundice (yellowing of the skin and eyes) indicates that acute GVHD has affected the liver.

While hospitalized, to minimize the risk of graft rejection and GVHD, allogeneic SCT/BMT patients are given drugs to prevent GVHD before and after the transplant that suppress the immune system. Use of these drugs, however, increase 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 harbour potentially harmful bacteria.

Patients over the age of 30 are more likely to develop acute GVHD than younger patients. Patients receiving stem cell/bone marrow from a female donor who has had two or more viable pregnancies also are more likely to develop 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 cyclosporine, alone or in combination with steroids (Prednisone, Dexamethasone) and methotrexate before and after 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 more severe stages, or if the patient develops chronic GVHD.

Although these drugs weaken the ability of the donor’s T cells to launch an attack against the patient’s organs and tissues, they do 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 include weight gain, fluid retention, elevated blood sugar level, mood swings and/or confused thinking and weakening of the bone mass. These side effects are temporary and disappear once use of these drugs is discontinued.

While GVHD is extremely rare in autologous transplants, it occurs in approximately 50% of patients who have an allogeneic (donor) transplant. All patients receiving stem cells/bone marrow from a donor, unless the donor is an identical twin, will receive drugs to try to prevent GVHD.

Of those who develop GVHD, many will experience only minor difficulties. About half will  experience significant problems. While GVHD can be a very unpleasant and sometimes fatal complication of an allogeneic SCT/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.

Chronic GVHD occurs anytime after 100 days post-SCT/BMT. It may develop as a continuation of acute GVHD or occur without any prior history of acute GVHD. Chronic GVHD is usually less serious. Again, it is most frequently associated with dry, itching, general redness of the skin, soreness or dryness of the mouth or eyes, digestive tract issues, lung and liver complications, changes in skin pigmentation, and bacterial infections. It may also cause hair loss, premature graying, weight loss, vaginal dryness, cough, shortness of breath, joint problems, and vision impairment.

Descriptions
Chronic GVHD can 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.

Management
To manage and treat GVHD, a number of drugs such as described above are used early on to help prevent or minimize GVHD.  However, some side effects of the drugs can interfere with the patients’ quality of life. Chronic GVHD and the medications used to treat it result in a profoundly immunocompromised state.

Antibiotics are usually taken to reduce the risk of infection while chronic GVHD is being treated. 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 (depending on the severity of the GVHD and blood counts) 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, have open wounds, sores or infections.

Patients with chronic GVHD are usually advised to avoid vaccinations with live viruses such as German measles, tetanus, polio, etc. (including avoiding people/children who have recently received those vaccines) until the GVHD problem is completely resolved and use of immunosuppressive drugs ends.

NOTE: All these restrictions and limitations vary greatly depending on the type of GVHD you have, what stage you’re in, the severity of your GVHD, your blood counts, how far along you are post-transplant, the meds you take as well as the side-effects you are dealing with. Always confirm everything with your doctor before doing anything. I, personally, am over-cautious and my goal is to avoid infections at all cost therefore I have become quite strict with myself and my environment. There are many things we cannot control, but if there’s anything I can do to help my healing process, then I will do it.

So, in general, what are the things to avoid with overall chronic GVHD, compromised immune-system and neutropenia (low neutrophil counts)? Depending on the type and severity of your GVHD, stay out of crowds (especially at peak times), avoid fresh plants, most fresh fruits (thick skin fruits are ok such as bananas, oranges, papaya) and fresh vegetables (cooked vegetables and fruit are ok), raw nuts, breads made with raw nuts, baking/handling live yeast, shellfish, seafood, raw fish and meat, rare-cooked meat, fish and eggs, and unpasteurized anything (including honey). Avoid salad bars and deli counters. Buy vacuum-packed lunch meats rather than freshly sliced meats. Avoid cured or smoked fish and meats. Eat or drink only pasteurized milk, yogurt, cheese and other dairy products and juices. Avoid soft-mold-ripened and blue-veined cheeses (including Brie, Camembert, Roquefort, Stilton, Gorgonzola and Blue). Drink filtered water and avoid well water, or boil it for one minute before using. Avoid until the GVHD problem is completely resolved and use of immunosuppressive drugs ends.

Don’t break anything (bones, tendons), or cut, burn or injure yourself as it might be a way in for virus, bacteria, fungus, which might become an infection. Avoid infections at all cost as it is the most common cause of death. If you have Peripheral Neuropathy (often a side-effect of chemo/meds) be careful in handling cold or hot things, as well as keeping your balance when taking stairs and walking (I have tingling and numbness in my hands and feet which means I need to be vigilant at all times).

Maintain proper mouth hygiene (floss everyday and brush your teeth with a soft-toothbrush after every meal and before bedtime), rinse mouth with an appropriate mouthwash (non-alcohol) or water/baking soda solution before and after meals and meds if you have mouth issues. Wash hands at all times (before and after preparing food, handling medication, going to the bathroom, shaking hands, touching things in public spaces) and limit touching your face, mouth, eyes, nose.

For dry mouth, drink water with a squeeze or slice of lemon (seems counter-indicative but in fact, the lemon helps moisturize and gives a boost to the salivary glands). Keep lips moisturized with lanolin-based lip balms.

Keep skin well moisturized as well to avoid dry, chapped skin. The level of moisturizing needed will depend on whether you have skin GVHD or not. Moisturizing daily also permits you to examine your body for any injuries or cuts, including unexplained bruises or changes in skin pigmentation.

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.

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 temporary can help everyone involved-patient, family and friends-better cope with this period of treatment.

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.

Chronic skin GVHD, steroid treatment, eye problems and weight loss/gain can all affect how you look. They may also affect how you think other people see you. This may affect your relationships, particularly sexual relationships. If you have a partner it may help to tell them how you’re feeling about yourself, and what your worries are.

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

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.

Death due to severe GVHD is usually a consequence of infectious complications. The 10-year survival of patients with mild chronic GVHD is approximately 80%, but is less than 5% for patients affected by severe chronic GVHD.

GVHD is not always a negative development following a stem cell/bone marrow transplant. This is because the immune system that attacks the host causing GVHD is also known to attack cancer cells. Researchers have found that patients with GVHD generally  have a lower risk of having a relapse of their cancer.

Coping with chronic GVHD
The length of time chronic GVHD lasts varies. For many people it gradually improves over a few months, but for some it can last longer. The average length of time to have chronic GVHD is between 1 and 3 years.

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

Chronic GVHD can be very difficult to cope with, especially when you have been through such a lot of treatment. You may have been free of symptoms before your transplant. So dealing with long-term, uncomfortable symptoms after your transplant can be hard to accept.

As a woman, early on-set menopause caused by chemo is also a possibility which will affect your hormones, skin, vaginal dryness, mood swings, hot flashes, etc. The emotional consequences of early menopause weighs heavy for women who are still in child-bearing years, especially if they do not already have children and was still hoping to have them. This also adds to the compound effect of GVHD and meds side-effects.

Bladder issues also occur as a side-effect of some of the meds taken and leakage can be challenging physically and emotionally. I am personally experiencing this particular issue which makes planning ahead essential. Since I need to drink lots of fluids to make up for my dry mouth, I need to be aware of accessibility of washrooms depending on where I go and how long I will be there. I’m not at the ‘Depends’ stage yet, but I can see how that could eventually be a possibility. I am seeing a urologist to help me with this issue and we are hoping it will resolve itself once I am off my meds.

When the time comes, it may be difficult to go back to work and get back to some sort of normal life again. This can sometimes mean that you have money worries on top of everything else. All these feelings and worries can make you feel low or depressed. It can help to share your feelings with your family, close friends, or the doctors and nurses caring for you. Some people find that counselling helps them to deal with their situation.

NOTE: All these facts have been found on various internet sites, literature provided by the Leukemia & Lymphoma Society, the Bone Marrow Transplant Program of BC, and from my own personal experience. Never believe everything you read at face value, make sure to do your own extensive research and consult with your doctor on everything. Each person, each case, each situation is different and must be considered according to your own issues, restrictions, limitations, capabilities.

Please note that the terms stem cell and bone marrow transplant are now acceptably interchangeable. Most bone marrow transplants are now done using stem cells instead of bone marrow harvest. For the recipient, the procedure, process and end results are the same.

Sources: Leukemia & BMT Program of BC; The Leukemia & Lymphoma Society; Medicalistes.org; cancerresearchuk.org; bettermedecine.com; medresidents/stanford.edu/teachingmaterials/bmt/cgvhd.pdf; U-Med Medical Centre; Livestrong.com; About.com

Marie-Chantal