Graft-versus-host disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]

Graft-versus-host disease (GvHD) is a common complication of allogeneic bone marrow transplantation in which functional immune cells in the transplanted marrow recognize the recipient as “foreign” and mount an immunologic attack. It is a pathologic condition characterized by recipient tissue damage that arise from immunological activation of donor T lymphocytes. Donor T cells typically mount a response against foreign host cells in the gastrointestinal system, liver, and skin. It occurs in 40-60% of patients undergoing stem cell transplant.^[1] Acute GvHD typically occurs within 100 days of transplant. Chronic GvHD occurs after 100 days from transplant.^[2] Nearly 40% of patients will develop some form of GvHD, whether it is acute or chronic.^[2]

The first observation of GvHD was noted in the 1920s when researchers studied chicken embryos and noted immunological activation in the presence of foreign material. Given the immunologic pathogenesis of the disease, corticosteroids were used, and it was noted that steroids could induce an excellent response.

The classification of GvHD is based on both severity and time of onset. The severity is based upon the stage and grade. The conglomeration of stages of GvHD of each organ affected gives rise to the overall grade. Each affected organ has a staging system (stages 1-4), depending on the degree of organ dysfunction. The time of onset determines whether GvHD is acute or chronic. Acute GvHD occurs within the first 100 days of stem cell transplant. Chronic GvHD occurs after 100 days from transplant.

The pathophysiology of GvHD involves immune activation of donor-derived T cells, which mount a response against host tissue, especially the liver, skin, and GI tract. Antigen-presenting cells (APCs) are key players in the initiation of the process. Immune activation leads to inflammation and organ destruction. Acute and chronic GvHD have slightly different pathophysiologic mechanisms.

The cause of GvHD is stem cell transplantation from an allogeneic donor, typically a donor that has few human leukocyte antigen (HLA) similiarities compared to the recipient.^[2]

Other possible etiologies for liver dysfunction in a patient who received stem cell transplant include CMV hepatitis and veno-occlusive disease. It is important to differentiate these etiologies from GvHD, as the treatment implications are different.

GvHD can occur in any population. Certain subsets of donor cells are less likely to result in GvHD, such as umbilical cord blood-derived stem cells, which contain fewer T cells than other sources of stem cells. There are no known racial disparities for GvHD. There are no particular geographic areas that are more prone to GvHD.

One major risk factor for GvHD is HLA-mismatched donor source. The greater the degree of mismatch, the greater the likelihood for GvHD. Another common risk factor is the use of total body irradiation as the conditioning regimen.

There is no role for screening (secondary prevention) for GvHD. However, there is a significant role for primary prevention in GvHD. Such primary prevention measures include medications like methotrexate and antibiotics like ciprofloxacin for gut decontamination.

The natural history of GvHD is variable from patient to patient. For mild forms of GvHD, the disease is expected to abate after immunosuppressive therapy is started. In severe cases of GvHD, the natural history is such that immune activation continues for quite some time, and the disease can be refractory to therapy. For steroid-refractory GvHD, the morbidity and mortality is very high, and the natural history of the disease terminates with organ failure and death.

The complications of GvHD stem from the resultant end-organ damage that occurs from immune activation. Complications include debilitating GI symptoms (including life-threatening diarrhea and abdominal pain), disruption of the GI mucosa and subsequent bacterial translocation and sepsis, liver failure, and skin infections.

The prognosis of GvHD is variable based on the severity of disease. Steroid-refractory GvHD has a much poorer prognosis then steroid-responsive GvHD.

The diagnosis of GvHD can be based via tissue biopsy of the suspected organ involved. For GI GvHD, endoscopy or colonoscopy with mucosal biopsies can be done to confirm the diagnosis. For liver GvHD, a liver biopsy can confirm the diagnosis. For skin GvHD, punch biopsies of the skin can confirm the diagnosis. Typical histologic findings include vacuolar interface dermatitis.

The symptoms are based on the organs involved. Skin symptoms include maculopapular rash and erythema. Liver symptoms include jaundice, pruritis, edema, and abdominal pain. GI symptoms include diarrhea, abdominal pain, and bleeding.

The physical exam of a patient with GvHD should focus on the organs involved. Skin exam findings include erythema and rash. Liver exam findings include tender hepatomegaly, edema, and jaundice. GI exam findings include abdominal tenderness.

For liver GvHD, abnormal liver function testing can be seen. This includes elevated alanine aminotransferase, elevated aspartate aminotransferase, hyperbilirubinemia, elevated alkaline phosphatase, elevated prothrombin time, and elevated partial thromboplastin time.

There is no specific role for imaging in GvHD. Chest X-ray can show evidence of pneumonitis if there is immunological attack in the lungs. CT of the abdomen can show inflammation in the intestines if there is evidence of GI GvHD.

Endoscopy and colonoscopy can be used to assess for inflammation the GI mucosa and can be used to help biopsy mucosa to determine a pathologic diagnosis for GI GvHD. Liver biopsy can be done to assess for a pathologic diagnosis of liver GvHD. Skin biopsy can be done to assess for a pathologic diagnosis of skin GvHD.

Medical therapy focuses on immunosuppressive medications, since GvHD is an abnormal and intense immunological phenomenon. Steroids are the first line of therapy. Other treatment options include alternative immunosuppressive medications like tacrolimus or mycophenolate.

There is no role for surgery in the management of GvHD. However, if GvHD becomes very severe to the point of organ dysfunction requiring surgery, surgery may be indicated in the correct clinical context.

Prevention of GvHD is based on primary preventive strategies, including use of donor stem cells that are closely HLA-matched to the recepient, the use of methotrexate in the first 11 days immediately post-transplant, and the use of anti-microbial agents to prevent GI inflammation and infection. There is no role for secondary prevention.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Shyam Patel [2]

The history of GvHD dates back to the 1910s, when an immunologic reaction was observed in chick embryos. Since that time, many advances have been made throughout the decades with regards to our understanding of the disease and treatment options for the disease. A seminal discovery in the history of GvHD was made by Billingham in 1966, which paved the way for a deeper understanding of the pathophysiology of GvHD.

GvHD was recognized many years ago in the early 20th century.

• In 1916, GvHD was first observed at the Rockefeller Institute in New York City. An immunologic reaction was noticed after engrafting adult chicken tissue containing T cells onto the chorioamnionic membrane of chick embryos.^[1] At that time, the concept of T cells was in its infancy. Prior to that time, there was no suggestion of a link between GvHD and T cells.^[1]

• In 1957, Billingham and Brent noticed unexpected findings. They noticed that mice who were chimeric were becoming very sick and were termed “runts.” It was eventually discovered that immunocompetent cells from neonatal inocula could migrate to areas of host lymphoid tissue and mount an attack.^[1] In the same year, Morton Simonsen showed evidence of GvHD in chickens. He had injected allogeneic lymphoid cells into chick embryos.^[1]

• In 1959, the work done by Billingham and Brent work was published.

• In 1962, Barnes and colleagues noted that mice who were lethally irradiated then treated with a bone marrow xenograft developed a secondary disease.^[2] This article was called “Secondary disease of radiation chimeras: a syndrome due to lymphoid aplasia.” This seminal paper helped to define what we know today about the pathophysiology of GvHD.^[2]

• In 1966, Billingham described 3 prerequisites for GvHD.^[2] The first prerequisite is the existence of immunocompetent cells in the donor tissue. The second prerequisite is the presence of allelic disparities, or histocompatibility differences, between the donor and the recipient. The third prerequisite is the impaired ability of the recipient to reject the donor cells.^[2] These findings paved the way for a better understanding of the pathophysiology of GvHD, and Billingham’s principles still hold true today.

• In 1978, Korngold and Sprent noted that the cellular mediators of GvHD are mature donor T cells.^[2]

• In 1990, Weisdorf and colleagues from the University of Minnesota made a seminal discovery after analyzing the long-term outcomes for patients with grades II-IV GvHD after stem cell transplant.^[3] After treatment with steroids, it was noted that 41% of patients achieved a complete remission after 3 weeks of therapy.^[3] There was a 5-year survival advantage (51% vs. 32%) in patients who had achieved complete remission from GvHD.^[3]

• In the 2000s, it was noted that multiple new classes of immunosuppressive medications could be used as an alternative to corticosteroids for treatment of GvHD.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]

Classification can be related to time-of-onset or to disease severity. Time-of-onset classification divides GvHD into acute or chronic, based on the key time point of 100 days. Severity classification divides GvHD into stages and grades, as defined by the International Bone Marrow Transplant Registry (IBMTR). The ultimate grade of GvHD is determined by the stages of the individual organs affected. Grade 1 GvHD, for example, is characterized by skin involvement but without liver or GI involvement.

• Clinically, graft-versus-host-disease is divided into acute and chronic forms.
  • The acute or fulminant form of the disease (aGVHD) is normally observed within the first 100 days post-transplant^[1], and is a major challenge to transplants owing to associated morbidity and mortality^[2].
  • The chronic form of graft-versus-host-disease (cGVHD) normally occurs after 100 days. The appearance of moderate to severe cases of cGvHD adversely influences long-term survival ^[3].
  • The overlap syndrome includes features of both acute and chronic GvHD. This is less commonly encountered.^[4]

• This distinction is not arbitrary: acute and chronic GvHD appear to involve different immune cell subsets, different cytokine profiles, somewhat different host targets, and respond differently to treatment.

• The severity classification is based on skin, liver, and GI involvement. The International Bone Marrow Transplant Registry (IBMTR) has created a staging and grading system.^[5] In this classification, GvHD is divided as follows:

Skin:

• Stage 0: no rash
• Stage 1: maculopapular rash < 25% of body surface area
• Stage 2: maculopapular rash 25-50% of body surface area
• Stage 3: maculopapular rash >50% of body surface area
• Stage 4: generalized erythema plus bullous formation

Liver:

• Stage 0: bilirubin < 2 mg/dl
• Stage 1: bilirubin 2-3 mg/dl
• Stage 2: bilirubin 3.1-6 mg/dl
• Stage 3: bilirubin 6.1-15 mg/dl
• Stage 4: bilirubin >15 mg/dl

GI:

• Stage 0: < 50cc stool per day or persistent nausea
• Stage 1: 500-999cc stool per day
• Stage 2: 1000-1500cc stool per day
• Stage 3: > 1500cc stool per day
• Stage 4: severe abdominal pain or ileus

The conglomeration of staging gives rise to a grade. The grading system is as follows:

• Grade 1: skin stage 1-2 with no liver or GI involvement
• Grade 2: skin stage 3 or liver stage 1 or GI stage 1
• Grade 3: skin with any stage or liver stage 2-3 or GI stage 2-4
• Grade 4: skin stage 4 or liver stage 4 or GI with any stage

• This type of GvHD is associated with transfusion of un-irradiated blood to immunocompromised recipients. It can also occur in situations where the blood donor is homozygous and the recipient is heterozygous for an HLA haplotype. It is associated with higher mortality (80-90%) due to involvement of bone marrow lymphoid tissue, however the clinical manifestations are similar to GVHD resulting from bone marrow transplantation. Transfusion-associated GvHD is rare in modern medicine. It is almost entirely preventable by controlled irradiation of blood products to inactivate the white blood cells (including lymphocytes) within.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]

The pathophysiology of GvHD is based upon immune activation and inflammation due to donor-derived T cell responses, ultimately resulting in host organ damage.^[1] Acute and chronic GvHD has slightly different pathophysiologic mechanisms.^[2] The pathophysiology begins with tissue damage from the preparative regimen, then ensues with donor T cell activation, followed by destruction of host tissue in the skin, liver, and/or GI tract. Various T cell subsets play different roles in the pathophysiology of GvHD, and Th1 cells are thought to be major contributors to the inflammation and destruction that underlies the pathophysiology of GvHD.

The general pathophysiologic processes for GvHD are described as follows:

Acute GvHD

The pathophysiology of acute GvHD involves donor alloreactive T lymphocytes mount an immune attack against recipient tissue.^[1] The most common tissues affected are the skin, liver, and gastrointestinal tract.^[1] Tissues of cardiac, skeletal muscle, or neurologic origin are typically not affected.^[1] The process begins with tissue injury that is produced by the conditioning regimen, before the transplant is even performed.^[3] This results in a cytokine storm and inflammatory environment.^[3] Donor T cells can recognize an antigen presenting cell (APC) harboring a minor histocompatibility antigen (miHA). APCs are typically dendritic cells, which are professional APCs.^[4] miHA are short protein fragments that are derived from intracellular proteins. When donor-derived T cells interact with these Mihas, the immune response is activated.^[5] CD4+ T cells recognize Mihas on MHC class II molecules, and CD8+ T cells recognize miHAs on MHC class I molecules. Both CD4+ and CD8+ T cells are known to play an important role in GvHD pathogenesis. Though both host and recipient APCs are present in a patient after a transplant, the host APCs are the key cells that allow for antigen presentation.

Chronic GvHD

One of the hallmark features of chronic GvHD is inflammatory fibrosis.^[6] In chronic GvHD, thymic epithelial cells are destroyed by alloreactive T cells.^[6] This results in decreased regulatory T cell production. Self-reactive T cells are released from the thymus. Furthermore, B cell homeostasis is disrupted, with resulting increased B cell activation and increased production of pre-germinal center B cells.^[6] It has been observed that patients with chronic GvHD have high CD21-negative transitional B cells and low CD27-positive memory B cells.^[6]

In 2006, Ferrara and Reddy proposed 3 specific stages in the pathophysiology of GvHD.^[7] These stages include:

• Stage I: Host tissue damage from the conditioning regimen. In this stage, proinflammatory cytokines are released.^[7]
• Stage II: Activation of donor T cells. In this stage, both host and donor APCs play a role in activating donor lymphocytes. The activated T cells produce a variety of proinflammatory cytokines.^[7]
• Stage III: Release of cellular and inflammatory mediators. In this stage, clinical manifestations develop due to cytokine-mediated damage,^[7]

T cell subsets

There are multiple T cell subsets involved in the pathophysiology of GvHD, and these have distinct roles in disease onset and progression.

• Th1-type cells: An important component in the immune response is the Th1-type subset and its cytokines TNF-alpha, IL-2, and interferon-gamma. This is typically a pro-inflammatory subset of cells that can exacerbate the disease. The Th1-type response drives acute GvHD.^[8]

• Th2-type cells: A Th2-type profile, which includes IL-4, IL-5, IL-6, IL-10, and IL-13, can suppress acute GvHD.^{[1] [4]} There are some exceptions to this observation, as elimination of interferon-gamma can enhance GvHD and loss of IL-4 can reduce GvHD. The Th2-type response is thought to drive chronic GvHD.^[8]

• Th17 subset: The Th17 subset has been shown to play a significant role in acute GvHD pathogenesis.^[8] Th17 cells are derived from naïve CD4+ T cells after exposure to IL-6 and TGF-beta. These cells coordinate local inflammation via release of cytokines like IL-17 and IL-23.^[4] IL-17 normally functions in anti-microbial immunity, but excess IL-17 production can result in autoimmunity and immune activation. This can contribute to worsening GvHD pathophysiology. Current data suggests that we do not have a solid understanding of the role of IL-17 and the Th17 subset in GvHD, but this is currently a focus on research efforts.^[4]

• Treg subset: Regulatory T cells (Tregs) normally function in suppression of immune activation, prevention of autoimmunity, and maintenance of immune homeostasis.^[6] In GvHD, the Treg repertoire is disrupted, and patients have lower Treg activity in chronic GvHD.^[6]

The programmed death-1 (PD-1) pathway is an immune checkpoint pathway that functions to suppress alloreactive T cells.

Current questions about the pathophysiology

We currently do not have a complete understanding about certain aspects of the pathophysiology. These unknown aspects include, but are not limited to:

• The target antigens in the epithelial crypts and bile ducts^[9]
• Mechanisms of endothelial damage in the GI tract^[9]
• Reason as to why epithelial hyperplasia does not repair damaged mucosa^[9]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]

The major cause of GvHD is HLA disparity between the recipient and host, resulting in abnormal immune activation against the recipient. This concept was proposed by Billingham in the 1960s.

According to the Billingham Criteria, 3 criteria must be met in order for GvHD to occur.^[1]

• Administration of an immunocompetent graft, with viable and functional immune cells.
• The recipient is immunologically disperate and histoincompatible.
• The recipient is immunocompromised and therefore cannot destroy or inactivate the transplanted cells.

After bone marrow transplantation, T cells present in the graft, either as contaminants or intentionally introduced into the host, attack the tissues of the transplant recipient after perceiving host tissues as antigenically foreign. The T cells produce an excess of cytokines, including TNF alpha and interferon-gamma (IFNg). A wide range of host antigens can initiate graft-versus-host-disease, among them the human leukocyte antigens (HLAs). However, graft-versus-host disease can occur even when HLA-identical siblings are the donors. HLA-identical siblings or HLA-identical unrelated donors often have genetically different proteins (called minor histocompatibility antigens) that can be presented by MHC molecules to the recipient’s T cells, which see these antigens as foreign and so mount an immune response.

While donor T cells are undesirable as effector cells of GvHD, they are valuable for engraftment by preventing the recipient’s residual immune system from rejecting the bone marrow graft (host-versus-graft). Additionally, 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 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.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2] M. Khurram Afzal, MD [3]

The differential diagnosis of GvHD is broad given the complexity of post-transplant patients. Infectious etiologies must be considered in persons who under stem cell transplant. A skin rash in the post-transplant setting, for example, could reflect infectious dermatitis or skin GvHD. Liver dysfunction in the post-transplant setting, for example, can reflect an infectious hepatitis of liver GvHD. Gastrointestinal symptoms in the post-transplant setting, for example, could reflect infectious enteritis/colitis or GI GvHD. Chronic graft-versus-host disease must be differentiated from other diseases that cause skin thickening such as scleredema, scleromyxedema, eosinophilic fasciitis, scleroderma, drug induced scleroderma, scleroderma overlap syndromes, diabetic cheiroarthropathy, myxedema, and nephrogenic systemic fibrosis.

The differential diagnosis for GvHD can be categorized into the specific organs involved. When a post-transplant patient develops skin, liver, or [Gastrointestinal tract|GI,]] symptoms, there are numerous possibilities regarding the etiology, as post-transplant patients are immunocompromised and at risk for infections. The clinical manifestations of infection in the skin, liver, or GI tract can mimic symptoms of GvHD.

For skin signs and symptoms, differential diagnosis includes:

• Varicella zoster (shingles)
• Bacterial cellulitis
• Fungal skin infection (tinea corporis)
• Toxic erythema of chemotherapy
• Drug eruption

For liver signs and symptoms, differential diagnosis includes:

• CMV hepatitis^[1]
• Sinusoidal obstruction syndrome (hepatic veno-occlusive disease)
• Viral hepatitis^[1]
• Cholelithiasis
• Choledocholithiasis

For gastrointestinal signs and symptoms, differential diagnosis includes:

• Typhilitis (neutropenic enterocolitis)
• Clostridium difficile colitis
• Viral gastroenteritis^[1]
• Ischemic colitis

• Chronic graft-versus-host disease must be differentiated from other diseases that cause skin thickening such as scleredema, scleromyxedema, eosinophilic fasciitis, scleroderma, drug induced scleroderma, scleroderma overlap syndromes, diabetic cheiroarthropathy, myxedema, and nephrogenic systemic fibrosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]

Overall, GvHD is a rare disease, given that this disease can only develop after a stem cell transplant is performed, and only a small fraction of people undergo stem cell transplants. However, amongst those who do undergo stem cell transplants, the incidence of GvHD is high (35-50%). The incidence of GvHD is estimated to be 9.5×10-7 per 100,000 cases. There are approximately 5500 total cases annually.^[1] Patients of all age groups may develop GvHD, but it occurs more commonly in older persons who receive stem cells from female donors. GvHD affects men more commonly than women. There is no racial predilection to GvHD. The incidence of GvHD is not directly correlated with age, as the disease is an iatrogenic condition that occurs after a transplant, rather than a natural disease.

• In developing countries, the prevalence of GvHD has not been studied, as bone marrow transplants are only performed in highly specialized centers.
• There is no data on the number of persons living with GvHD.

• Worldwide, the incidence of GvHD ranges from a low of 8×10^-7 per 100,000 persons to a high of 1.14×10-6 per 100,000 persons with an average incidence of 9.5×10-7 per 100,000 persons.^[1] The reason for the low incidence worldwide is that the disease can only occur after a bone marrow transplantation, and bone marrow transplantations occur only in highly specialized centers.
• In developing countries, the incidence of GvHD has not been studied, as bone marrow transplants are only performed in highly specialized centers.
• In 2003, the incidence of GvHD was estimated to range from 4795 to 6850 total cases worldwide.^[1]

• The annual case fatality rate of GvHD is approximately 25%.^[2]

• GvHD is more likely to occur in persons of older age. However, given that this is not a natural disease, but rather an iatrogenic disease, GvHD can occur at any age, depending on when a patient underwent a bone marrow transplant.

• Males are more commonly affected with GvHD than females. The male to female ratio is approximately 1.4:1.^[3]

• The prevalence of GvHD does not vary by race.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]

The most potent risk factor for GvHD is disparity in HLA alleles between the recipient and donor. Some risk factors depend on demographics of the recipient and donor.

Risk factors for GvHD include:

• High degree of HLA disparity between host and donor cells^[1]
• Use of unrelated donors as the stem cell source^[1]
• Total body irradiation as the conditioning regimen prior to transplant^[1]
• Prior acute GvHD^[2]
• Use of peripheral blood stem cells^[2]
• Use of a T cell replete graft^[2]
• Viral infection, since this can contribute to immune activation^[2]
• Male host^[2]
• Multiparous female donor^[2]

Protective factors include:

• High degree of HLA concordance between the host and donor
• Use of umbilical cord blood as the donor source (given decreased number of donor T cells)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]

Screening of the general population for GvHD is not recommended.

Screening of the general population for GvHD is not recommended. This is because GvHD can only occur in persons who undergo stem cell transplant, and only a very small fraction of persons will undergo stem cell transplant. The cost of screening to identify persons at risk would outweigh the benefits.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]

GvHD carries a high morbidity if not appropriately treated, and its natural history can result in organ failure and eventually death. Complications of GvHD include infection, organ damage and, in rare cases, squamous cell carcinoma or other immunosuppression-associated hematolymphoid malignancies. Poor prognostic factors include thrombocytopenia, severe jaundice, older age, >1 liter of diarrhea per day, hypoalbuminemia, and gastrointestinal ulceration. Multiple prognostic tools have been developed, including Johns Hopkins Hospital classification, Center for International Blood and Marrow Transplant Research classification, and the NIH consensus classification.

The natural history of GvHD begins with a stem cell transplant and immunological interactions between donor cells and recipient tissue. Within a short period of time, even within a few days, a clinically significant immunologic response occurs. The natural course of the disease progresses to organ dysfunction in the skin, liver, and GI tract. This dysfunction can last for many weeks and even longer if left untreated. If treated appropriately with immunosuppression, the natural history of GvHD can be hampered, with inhibition of ongoing organ damage. If left untreated, worsening skin, liver, GI, and pulmonary manifestations will inevitably occur as the donor immune cells destroy host tissue. This can lead to:

• Skin breakdown with subsequent infections and sepsis

• Worsening cholestatic hepatitis with hyperbilirubinemia and kernicterus

• Worsening GI dysfunction including high-volume diarrhea and dehydration, as well as sepsis from breakdown of intestinal mucosa

• Respiratory failure if there is pneumonitis

The natural history of GvHD can last for years, with a relapsing and remitting course. Different patients have different manifestations of the disease, and the natural history is thus variable. If patients develop steroid-refractory GvHD, the natural history tends to take an unfavorable course, with high morbidity and mortality. In this case, alternative immunosuppressive medications can be tried. However, the success rate for treatment of steroid-refractory GvHD is low, and the natural history of the disease results in death within a relatively short time.

• Infections: A major complication of GvHD is the resulting immunosuppression that occurs after treatment. Treatment of GvHD focuses on abrogating the abnormal immune activation, and high dose steroids are typically administered. Late fungal infections and Pneumocystis carinii are common in patients who develop GvHD and receive treatment with immunosuppressive agents.^[1]

• Non-malignant late complications: These include ophthalmic, skeletal, joint, cardiovascular impairment.^[1]

• Malignant complications: These include squamous cell carcinoma of the head and neck (due to HPV infection), squamous cell carcinoma of the skin, and other immunosuppression-associated malignancy like hematolymphoid malignancies.^[1]

A few different prognostic classifications have been developed for GvHD.^[1]

• Johns Hopkins Hospital
• Center for International Blood and Marrow Transplant Research
• NIH consensus classification: This classification proposes a global chronic severity score and includes the degree to which different organs are involved.

Prognostic factors include:

• Thrombocytopenia with platelet count less than 100000 per microliter^[1]

The risk of mortality is based upon certain clinical features^[2]:

Low risk^[2]:

• Nausea
• Vomiting
• Early satiety
• Anorexia
• Stable albumin
• Less than 1 liter per day of diarrhea
• No other features found in the high or very high risk categories below

High risk^[2]:

• Young age
• Upper GI symptoms
• Jaundice of mild severity
• 1 liter per day of diarrhea
• Extensive skin rash
• Decline in albumin by more than 0.5 g/dl

Very high risk^[2]:

• Severe jaundice
• Older age
• Greater than 1 liter per day of diarrhea
• Hypoalbuminemia with albumin level than 1.6 g/dl
• GI ulceration

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