Bone marrow transplant is a revolutionary procedure in medicine, and has opened new perspectives in the management of many blood disorders. It can be curative in some conditions such as thalassemia, acute leukemias, hemoglobin disorders, some immunodeficiency disorders, and some autoimmune diseases. But like all medical procedures, it comes with its share of side effects and complications. The most significant is the graft versus host disease or GVHD.
What is GVHD?
Living organisms are fascinating, and the most fascinating part of their existence is the presence of a complex system of cooperation between multiple cells. According to evolutionary theory, the most important step of evolution is the transformation of unicellular organisms into multicellular organisms, and they key to reach this level of understanding between cells can be explained by antigens. If you walk into a building that has some form of security, the porter or security officer will ask for an ID, a method to make sure that you belong to that building. Our cells identify each other by a unique set of proteins placed on their surface. This mechanism doesn’t only serve to help cells identify each other, but also acts as a defense barrier against foreign cells or substances. Then, what the body doesn’t identify, it attacks.
Our immune system is complex and has some static components in the form of natural barriers like the skin, mucous membranes, stomach acidity and some adaptive mechanisms including the white blood cells. White blood cells are formed mainly in the bone marrow and if this bone marrow is transplanted to another patient, white blood cells and their “coding system” will transfer along with it. During the bone marrow transplantation process, the old bone marrow is usually ablated using chemotherapy or radiotherapy and the new one becomes the backbone of the patient’s immunity. In case of transplanted organs like the liver or the kidney, if the antigens are not similar between the donor and the recipient, tissue rejection will occur and that tissue or organ will be destroyed, sometimes even before closing the surgical wound. In the case of bone marrow transplantation, it is the transplanted bone marrow that attacks the recipient’s body, making the condition more severe.
It is worth knowing, however, that GVHD doesn’t only occur due to stem cell transplantation of the bone marrow, but can theoretically occur with the transplantation of any tissue containing white blood cells including blood products which have not undergone external irradiation – a standard procedure that aims to paralyze white blood cells of transfused blood- and in the case of particular types of tissue like the small intestines, which may contain a type of lymphoid tissue called Peyer’s patches.
What makes it more likely to happen
As mentioned above, GVHD is an unfortunate result of even modern stem cell transplantation and its occurrence is related to several factors, the most important of which are:
1) Mismatching
The more unlike the stem cells are to the body in which they are transplanted, the more likely for GVHD to occur. This includes different sex between the donor and the recipient and different HLA typing. That is why we consider twins to be the perfect donor-recipient, siblings follow and are followed by first degree relatives. For unrelated donors, we run HLA typing to ensure the greatest degree of similarity between the donor and the recipient.
2) Old age
Older patients have been found to have a greater risk of graft rejection, making them less ideal candidates compared to younger ones.
3) Preservation technique and the type of the graft
Some technical details regarding preservation of the graft can reduce the risk of GVHD. It is also shown that umbilical cord grafts have a better chance than those taken from the bone marrow in avoiding GVHD.
4) Chemotherapy
Chemotherapy is given after the transplantation for many reasons including ablating all malignant cells in blood cancers and -ironically- avoiding GVHD, however, their effect can be a double-edged weapon and a large amount of cytokines may be released into the circulation, triggering what is known as a cytokine storm, which greatly increases the risk of GVHD.
Types
1- Acute GVHD: Acute GVHD develops within 3 months of the transplantation process, and its symptoms mainly involve the intestines, the skin and the liver.
2- Chronic GVHD: Chronic GVHD is more complex than the acute type, and its symptoms are less defined. It occurs after more than 100 days following transplantation and can virtually occur after years. There is a clinical debate regarding whether or not it follows acute GVHD. So far, cases following acute GVHD, those that didn’t have acute GVHD and even those who had acute GVHD disease and recovered have been reported. The body systems involved are also more diverse and include the eyes, the joints, the gastrointestinal system, the muscles, the nerves and even the lungs.
Symptoms
As mentioned above, symptoms differ according to the type of GVHD.
A) Symptoms in acute GVHD include:
1) Skin manifestations
Skin manifestations are a good indicator of the severity of acute GVHD. The usual finding is a rash that is itchy and painful. In more severe cases, severe redness of the skin and falling off of the superficial layer may occur. Skin manifestations occur mostly in the 1st month following transplantation.
2) Liver manifestations
The liver is a silent organ and liver diseases do not cause symptoms unless severe and sudden. Therefore, in many cases, liver affection goes unnoticed, but in more severe cases, jaundice may develop. Jaundice occurs when a large portion of the liver is destroyed, and it can’t process the normal bilirubin resulting from the normal destruction of red blood cells. Bilirubin is yellow and attaches to elastic tissue and collagen found in the sclera or “the white of the eye” and the skin. Another rare manifestation of liver disease is coma.
Hepatic coma results from the accumulation of ammonia and manganese, which it normally excretes and processes. They act on brain cells causing a variety of manifestations including loss of coordination, short-term memory, confusion, disorientation or behavioral changes.
3) Gastrointestinal system manifestations
Gastrointestinal manifestations of acute GVHD include diarrhea which is profuse and watery. The main characteristic of this diarrhea is that it continues if the patient stops eating. This owes to its mechanism of destruction of the cell lining of the intestines. In some rare cases, indigestion with decreased appetite can occur without diarrhea.
B) On the other hand, chronic GVHD has a wider range of symptoms which include:
1) Eye manifestations
Dry eye is one of the major manifestations of many autoimmune diseases. It owes to autoimmune cells attacking cells of the lacrimal glands responsible for tear production. Symptoms include burning and increased light sensitivity.
2) Oral and esophageal manifestations
Cells lining the mouth are also targeted by immunity, leading to dry mouth and oral pain. Affection of the esophagus and the throat can cause difficult or painful swallowing.
3) Lung manifestations
The airways are affected by a condition called bronchiolitis obliterans and symptoms similar to asthma occur with prolonged expiration and shortness of breath.
4) Muscular manifestations
Although not usually life-threatening. They tend to be the most troublesome and unbearable and can range from mild cramps to severe neuropathic pain -like the one you feel when you have a carious tooth but in your muscles.
Diagnosis
Diagnosing GVHD depends on an accurate history taking and clinical examination supported by investigations, whether laboratory or radiological. Your doctor will make sure that your complaint is related to the graft you have received and not another independent condition, in a process known as differential diagnosis. The main challenge in GVHD is that it affects many organ systems making excluding other diseases challenging.
Your doctor will then examine your skin for jaundice or red lesions, your eyes for bleeding or dryness and your mouth for ulcers or specific lesions. They will then order a battery of lab investigations which include a full blood picture, liver enzymes, bilirubin level -which is responsible for the jaundice- and the level of sodium, potassium and proteins which tend to be affected in case of the severe watery diarrhea.
Regarding radiological investigations, they are of particular importance in cases of jaundice to check the liver anatomy by ultrasonography or the biliary tree to exclude other causes of the jaundice. If you present with painful or difficult swallowing, then another group of diagnoses regarding the esophagus and stomach have to be excluded such as motility disorders or esophageal cancer. Tests include a barium swallow Which is a viscid material that, when X-rays are performed after swallowing, we can accurately delineate esophageal anatomy and the presence of esophageal or stomach pathologies.
In some cases, your doctor may decide to take a biopsy, which is a piece of tissue, either from the skin, the esophagus, or your intestines. This can help establish the diagnosis as well as assess the severity of the condition. There is no need to worry about the pain, however, as most of those procedures are done either under local or general anesthesia.
Treatment
The treatment of GVHD is challenging since it is a natural consequence, and not technically a side effect. The key to successful treatment, then, is to prevent rather than treat the established condition. Treatment of both acute and chronic GVHD is medical in the most part with a minor surgical role in the interventions needed to deliver some medical treatments such as a central venous catheter.
A) Treatment of acute GVHD:
The treatment of acute GVHD is centered around preventing it by using a standard regimen of chemotherapy such as methotrexate, cyclosporine and tacrolimus. These are usually the main drugs administered in all cases, especially those with unrelated donors because of the higher risk of GVHD. Other non-chemotherapy options that are usually used adjunctly with chemo include plasmapheresis, where lymphocytes -the cells which have the greatest role in GVHD- are killed by external agents, or through ATG which are antibodies directed towards them.
If acute GVHD is established with symptoms, treatment depends on the severity and the number of organs involved. Doctors have a system of classifying the severity of the disease using roman numerals I, II, III, iv etc. and they employ treatment regimens in a stepwise approach.
• Regarding skin manifestations of acute GVHD, the first option in mild disease is local steroids. Corticosteroids remain the most effective non chemotherapy immunosuppressive. If the disease is progressive, the addition of steroids whether orally or by injection plus the original immunosuppressive chemotherapy used as a prophylaxis is the mainstay of treatment.
• The use of anti-thymocyte globulin or targeted therapies is also advocated in some conditions. Stem cell therapy has undergone excessive clinical trials and is showing promise.
• If the above treatment is ineffective, higher doses of steroids, monoclonal antibody therapy including infliximab as well as targeted therapy like etanercept are used. Another approach can be taken by administering high doses of chemotherapy like mycophenolate mofetil, one of the most potent immunosuppressive drugs. Ultraviolet irradiation is also beneficial for skin manifestations.
B) Treatment of chronic GVHD:
Although prophylaxis or “giving a drug for fear of” is quite well delineated in acute GVHD, it is less so in chronic GVHD. The main reason behind this is that the mechanism of chronic GVHD is less well-known, owing to the multitude of factors at play and the time lapse between the grafting and symptoms. With that said, two main measures are done as a prophylaxis for chronic GVHD:
- The use of anti-thymocyte globulin -antibody- before the grafting.
- The use of cyclophosphamide, which is a chemotherapeutic agent, during the first week following the grafting.
If chronic GVHD is established, several lines of treatment can be employed and tailored according to the patient’s response. Initial therapy consists of many agents used in acute GVHD like cyclosporine, tacrolimus and steroids. If initial therapy fails, several options exist for secondary therapy albeit with reduced efficacy:
- Mycophenolate mofetil with steroids have a greater response rate than other agents combined with steroids. Steroid resistance is especially challenging because they remain the cornerstone of treatment and the previous combination can be the best option for such condition.
- PUVA or ultraviolet radiation with psoralen especially for skin manifestations.
- Rituximab, one of the agents used in chronic leukemia can be used. It is specific against a receptor on lymphocytes called CD-20.
- Low dose radiotherapy.
- Ibrutinib which is also an agent used in leukemia.
You will notice that many regimens that are used in cancer are also employed against GVHD. This is because the main goal of immunosuppression is central in the management of both conditions.
What are my odds?
Technicalities aside, the most important question that has been hovering in your mind is how bad the condition is, or what is the risk of death in such cases. To put it simply, it varies widely according to the severity of the condition and the response to initial therapy. If secondary therapy were as effective as the initial, there would be no additional therapy, but they have some severe side effects and tend to not increase survival. The more severe the condition is, and the more organ systems involved, the less likely for the disease to be manageable.
Causes of death are diverse according to the organ most affected. The disease itself can cause death by depleting your blood of platelets and causing severe hemorrhage, weak immunity -despite the vigorous autoimmune reaction- leading to increased susceptibility to infections or liver affection in acute cases and liver failure. The medications used also have strong immunosuppressive effects, predisposing to infections.
Preventing GVHD remains the main goal in management and the greater contributor to overall survival.