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Graft Versus Host Disease


Graft Versus Host Disease

Article Author:
Angel Justiz Vaillant
Article Author:
Pranav Modi
Article Editor:
Oranus Mohammadi
Updated:
10/13/2020 1:58:40 PM
For CME on this topic:
Graft Versus Host Disease CME
PubMed Link:
Graft Versus Host Disease

Introduction

Graft-versus-host disease (GvHD) is a systemic disorder that occurs when the graft's immune cells recognize the host as foreign and attack the recipient’s body cells. “Graft” refers to transplanted, or donated tissue, and “host” refers to the tissues of the recipient. It is a common complication after allogeneic hematopoietic stem cell transplant (HCT) [1]

GVHD has been classically classified based on the timing of presentation into acute and chronic using a cutoff of 100 days post-transplant. This has been further subclassified based on clinical manifestations accepted by the NIH into:

  1. Acute classic GVHD: Presents within 100 days of transplantation with classical clinical features of acute GVHD.
  2. Persistent, recurrent, or late-onset acute GVHD: Manifests with clinical features of classic acute GvHD but after 100 days of transplantation.
  3. Classic chronic GVHD: Presents after 100 days of transplant with classic clinical features of chronic GvHD.
  4. Overlap syndrome: May present at any time post-transplant with features of both acute and chronic GvHD [1].

Etiology

GvHD occurs in the following settings:

  • Following allogeneic bone transplantation (most common)
  • Following transplantation of solid organs that are rich in lymphoid cells (eg. liver)
  • Following transfusion of un-irradiated blood

For GvHD to occur, immunologically competent cells should be transplanted into immunodeficient recipients and the transferred cells should recognize alloantigens in the host. Other important factors that determine the occurrence and severity of GvHD are:

  1.  Donor-host factors: The incidence of GVHD increases with unmatched donor transplants, HLA disparity, sex mismatching.
  2. Stem-cell source factors: cryopreservation of marrow prior to its infusion and the use of umbilical cord blood lower the incidence of GvHD.
  3. Immune modulation factors: The incidence of GvHD is lower with triple therapy (cyclosporine, methotrexate (MTX), and prednisone as compared with double therapy (cyclosporine and MTX) [2]. In the pre-clinical setting, statins can inhibit APC function and reduce the expression of MHC class II [3].
  4. Chemotherapy and radiation therapy: High-dose chemotherapy leads to local tissue damage and increases in the level of circulating cytokines that lead to a cytokine storm. This increases the ability of immune cells in the graft to recognize host antigens. An increased incidence and severity of GvHD is associated with regimens that include total body irradiation as compared with chemotherapy alone [4].  

Epidemiology

Acute GVHD can occur in up to 50% of patients receiving hematopoietic stem cell transplantation (HCT) from a human leukocyte antigen (HLA)-matched sibling [5] [6]. The occurrence is typically higher in unmatched donors. The incidence of chronic GVHD ranges from 6% to 80% [7]. GVHD is considered one of the main causes of morbidity and mortality after HCT; more than 10% of patients will die from this complication [8].

Risk factors of acute GVHD are higher degrees of HLA mismatch, prior acute GVHD gender disparity, older age of the donor and/or recipient, peripheral stem cell recipients, alloimmunization of the donor, Cytomegalovirus and Epstein Barr virus seropositivity [9]

Pathophysiology

Cells of the immune system are trained early to differentiate between "self" cells and "non-self" cells. The ability to recognize "non-self" cells depends on a set of genes knows as the histocompatibility genes that provide instructions for making a group of related proteins known as major histocompatibility complex (MHC proteins) or human leukocyte antigens (HLA). The histocompatibility genes code for MHC class I proteins that are present on all nucleated cells in the body and MHC class II molecules that are expressed only on antigen-presenting cells. During transplantation, the donor tissue is usually obtained from a genetically different individual known as an "allograft". Immune cells in the graft recognize the  MHC proteins of the recipient tissue as "non-self" and triggers an immune response between the donor and the recipient.

Donor cytotoxic CD-8 t cells recognize host tissue as foreign and proliferate to cause severe organ damage (type IV cytotoxic T cell hypersensitivity reaction). Donor allograft T-cells are the main effector cells for GvHD and its pathogenesis can be divided into three phases (Figure 1) [10].

  • Phase 1 (afferent phase): Radiation or chemotherapy prior to bone marrow transplantation causes recipient tissue damage. This leads to increased levels of inflammatory cytokines (IL-1, IL-6, TNF alpha) and expression of MHC antigens that enhance APCs (antigen-presenting cells) to present alloantigens to the donor T cells.
  • Phase 2 (efferent phase): This phase is characterized by the interaction of donor T cells with host APCs that proliferate and differentiate into activated T cells which then release additional inflammatory cytokines (IL-2, INF-γ).
  • Phase 3 (effector phase): The third phase is characterized by the migration of cytotoxic T lymphocytes and natural killer cells migrate to target organs and cause tissue damage leading to multiorgan failure.

Histopathology

In the gastrointestinal tract, apoptosis of epithelial cells is the most important feature. Dilated crypts, crypt destruction, villus atrophy, neutrophilic infiltration can also be seen in small bowel specimens [11]. Liver biopsy shows dysmorphic small bile ducts with portal inflammation. Histopathological damage of the skin ranges from minimal vacuolization to separation of the dermis from the epidermis. Grades of skin graft-versus-host-disease are as follows (Figure 2): [12]

  • Grade I: minimal vacuolization in the epidermis
  • Grade II: vacuolization and dyskeratotic bodies
  • Grade III: subepidermal cleft formation
  • Grade IV: separation of the dermis from the epidermis

History and Physical

Acute GVHD usually involves the skin, gastrointestinal tract, and liver, and is seen in 70%, 74%, and 44%, respectively. It can also involve the lungs, kidneys, eyes, and hematopoietic system. It may also result in decreased responsiveness to active immunization. 

The most common skin manifestation is a pruritic or painful maculopapular rash that initially involves the palms, soles shoulders, and nape of the neck. It can spread diffusely and become confluent. In severe GVHD, bullous lesions with toxic epidermal necrolysis mimicking TEN can develop.

GI symptoms most commonly include diarrhea and abdominal pain, but mucositis, mucosal ulceration, nausea, and vomiting can also occur. Diarrhea is secretory and continues despite fasting. Diarrhea initially is watery, but may progress to become bloody, and may require frequent blood transfusions and cause difficulty in maintaining adequate fluid balance. 

Liver involvement usually presents together with either cutaneous or GI manifestation, it rarely occurs in isolation. Abnormal liver function tests are characteristic, typically with elevated bilirubin and alkaline phosphatase levels. Coagulopathy and hyperammonemia are rare but can occur in severe forms. Hepatomegaly, as well as, pale urine and stool may be present. 

Chronic GVHD has many features in common with collagen vascular disorders and systemic sclerosis [13]. In the oral cavity, chronic GVHD may present as lichen planus with a risk of development to oral squamous cell carcinoma that differs from the classical pathology and seems to be more aggressive in patients with stem cell transplantation [14]. Recurrent infections can be a cause of death, and it is often a complication of immunosuppression [15][16]. Ocular involvement is an indicator of poor prognosis in GVHD. It usually affects the ocular surface and manifests with dry eye or keratoconjunctivitis sicca [17].

Evaluation

Diagnosis is usually clinical. Traditionally the criteria as described by Billingham include the following: [18]

  • Immunologically competent cells must be present in the graft.

  • The recipient should have transplantation alloantigens that appear foreign to the graft and can therefore stimulate it antigenically.

  • The recipient should not be capable of mounting an effective immunologic reaction against the graft, or it must allow for enough time for the graft to manifest an immune response.

All patients who underwent hematopoietic cell transplantation are at potential risk of GVHD, although it usually occurs during the first few months post-transplantation [19]. Skin and gastrointestinal (usually rectal) biopsies can help confirm the diagnosis. The staging of the disease is based on the extent of symptoms and lab abnormalities.

The use of biomarkers for the diagnosis and prognosis estimation is an area of investigation. Currently, no biomarker is ready for clinical application, but examples include ST2, REG3alpha, and TNFR1 [20] [21] [22].  

Treatment / Management

All patients receiving HCT should undergo prophylactic treatment for GVHD. Treatment protocols differ by institution, but most commonly use a combination of cyclosporine and methotrexate is continued for several months post-transplantation. Antibacterial, antiviral, and antifungal prophylaxis is typically added post HCT to mitigate the risk of infections. 

Treatment for GVHD depends on the severity of symptoms and organs involved. Most treatment options focus on immunosuppression of donor T cells and must be balanced to reduce the symptoms of GVHD while avoiding decreasing the beneficial graft vs. tumor (GVT) response. Corticosteroids remain the most commonly used treatment.

Grade 1 GVHD is usually managed with topical steroids in an attempt to control local symptoms. Topical tacrolimus is an option for steroid-resistant disease. 

Grade 2 or higher requires the addition of systemic steroids, most commonly methylprednisolone 2 mg/kg/day in divided doses. In cases of GI involvement, the addition of a nonabsorbable corticosteroid (budesonide or beclomethasone) is more effective than systemic treatment alone. Steroids should be avoided if a GI infection is present. 

Gradual tapering of the steroid over the course of several months is important to prevent a GVHD flare. Patients with chronic GVHD will typically require prolonged courses of steroids, generally 2 - 3 years. Some patients may require lifelong treatment. Octreotide can be added in an attempt to decrease the amount of diarrhea. 

The addition of other agents to steroids include mycophenolate, etanercept, pentostatin, monoclonal antibodies, sirolimus, alpha-1-antitrypsin, mesenchymal stromal cells, and extracorporeal photopheresis. However, their efficacy is unclear. 

Cyclosporine can be added to the treatment regimen for chronic GVHD in an attempt to decrease steroid dosage and duration. 

Differential Diagnosis

The differential diagnosis depends on the clinical manifestations:

Skin GVHD

Drug reactions, viral exanthems, radiation dermatitis

Hepatic GVHD 

Infection, especially viral hepatitis, drug-induced liver injury, shock liver, immunotherapy-related hepatotoxicity, sinusoidal obstructive syndrome, and malignancy [23]

GI GVHD  

Diarrhea: iatrogenic (secondary to chemotherapy, immunosuppressants, antibiotics or magnesium), infectious (CMV, EBV, Adenovirus, Rotavirus, Clostridium difficile, Mycobacterium avium complex, Giardia, Cryptosporidium), thrombotic microangiopathy, bile-salt malabsorption

Nausea and vomiting, anorexia: iatrogenic (secondary to chemotherapy, immunosuppressants, radiation, antibiotics, opioids) [24].

Pertinent Studies and Ongoing Trials

 

 

 

Treatment Planning

 

 

Staging

The two most famous systems for acute GVHD staging are the International Cone Marrow Transplant Registry (IBMTR) system (A-D) and Glucksberg grade (1-4) [25][26]. Staging is based on clinical manifestations and severity of organ involvement [6].

Skin     

  • Stage 1: Maculopapular rash less than 25% of the body
  • Stage 2: Maculopapular rash 25% to 50% of the body
  • Stage 3: Generalized erythroderma
  • Stage 4: Generalized erythroderma with bullae

Liver

  • Stage 1: Bilirubin 2-3, AST 150-750
  • Stage 2: Bilirubin 3-6
  • Stage 3: Bilirubin 6-15
  • Stage 4: Bilirubin >15

GI system

  • Stage 1: Diarrhea >500 cc/day
  • Stage 2: Diarrhea >1000 cc/day
  • Stage 3: Diarrhea > 1500 cc/day
  • Stage 4: Diarrhea > 2000 cc/day or severe abdominal pain

Glucksberg grade [26]

  1. Mild: no liver or GI involvement, stage 1-2 skin involvement
  2. Moderate: stage 1 liver or GI involvement, stage 1-3 skin involvement
  3. Severe: stage 2-3 skin, liver, or GI involvement
  4. Life-threatening: stage 2-4 liver or GI involvement, stage 1-4 skin involvement

International Cone Marrow Transplant Registry (IBMTR) Severity index [26]:

  1. Mild: no liver or GI involvement, stage 1 skin involvement
  2. Moderate: stage 1-2 liver or GI involvement, stage 2 skin involvement
  3. Severe: stage 3 skin, liver, or GI involvement
  4. Life-threatening: stage 4 skin, liver, or GI involvement

Prognosis

Mortality is generally higher in moderate to severe GVHD in comparison with mild disease [8] [27]. The 5-year survival rate of grade C is 25%, while grade 4 has a survival rate of 5% [28]. There is a strong correlation between the response to first-line treatment and survival [6]

Extensive skin involvement, diarrhea, thrombocytopenia, elevated liver enzymes, and involvement of the lung or liver are poor prognostic factors for acute or chronic GVHD [29] [1].

Complications

GVHD is a complication of allogeneic hematopoietic stem cell transplant that can usually have other complications, including bronchiolitis obliterans syndrome, interstitial lung disease, obliterative bronchiolitis, organizing pneumonia, and pleuroparenchymal fibroelastosis.[30]

Reported complications include gastrointestinal involvement resulting in fibrosis, motility abnormalities, and malabsorption. Lung problems may cause bronchiectasis. Infection is common and fatal.

Liver complications include endothelialitis, bile duct destruction, and pericholangitis, but a liver biopsy is not done routinely due to associated thrombocytopenia.[5]

Consultations

Nutritionists should evaluate patients with GI involvement due to a higher risk of malnutrition and abnormalities in zinc, magnesium, vitamin B12, and vitamin D [31]

Deterrence and Patient Education

Along with the timely appropriate treatment and prophylactic measures, patients can receive counseling and education about some remedial measures to improve the management of GVHD.

Skincare: Usage a moisturizer, application of sunscreen lotion with appropriate SPF when going out to the sun, avoid scratching on the sutured area, or other regions, wearing long sleeves and pants.

Mouth care: dental hygiene with topical fluorides is suggested [32]

Diet: Utmost care on choosing what to eat. Better to avoid substances that can cause loose stools such as spicy food.

Hygiene: Staying away from infective sources, wearing a face and nose mask when going out, keeping the hands and feet clean. 

All the patients and caregivers should take vaccines against influenza and pneumococcus [5]

Enhancing Healthcare Team Outcomes

An interprofessional team should educate the parents and manage patients with a likelihood of developing GVHD. Primary care providers should refer patients known to have T-cell immunodeficiency to a hematologist to prevent infections and other complications. Coordination of care must occur between the transplant team and the patient's primary provider to optimize treatment and avoid complications. Transplant nurses monitor patients, report issues, and provide patient and family education. [Level 5]



(Click Image to Enlarge)
GVHD Pathogenesis (Figure 1)
GVHD Pathogenesis (Figure 1)
Contributed by Reddy, P. and Ferrara, J.L.M., Mouse models of graft-versus-host disease (February 28, 2009), StemBook, ed. The Stem Cell Research Community, StemBook, doi/10.3824/stembook.1.36.1, http://www.stembook.org/node/548 ., CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=25463572

(Click Image to Enlarge)
Grades of skin graft vs host disease
Grades of skin graft vs host disease
Contributed by Sakhila Ghimire, Daniela Weber, Emily Mavin,Xiao nong Wang,Anne Mary Dickinson and Ernst Holler1 - (2017). "Pathophysiology of GvHD and Other HSCT-Related Major Complications". Frontiers in Immunology 8. DOI:10.3389/fimmu.2017.00079. ISSN 1664-3224. CC-BY 4.0

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