Graft Versus Host Disease


Article Author:
Angel Justiz Vaillant
Oranus Mohammadi
Abdul Waheed


Article Editor:
Daniel Heller


Editors In Chief:
Stephen Leslie
Karim Hamawy


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
7/8/2019 9:02:58 AM

Introduction

Graft-versus-host disease (GVHD) occurs secondary to an organ or tissue transplantation and must fulfill these criteria:

  1. Histocompatibility differences between the graft (donor) and the host (recipient)  
  2. Presence of immunocompetent T lymphocytes in the graft   
  3. An immunodeficient recipient, whose immune system is not competent enough to mount an effective immune response against the foreign T cells  
  4. Occurring before an arbitrary 100-day period and clinical manifestations may occur after 100-day post-graft   
  5. Signs of tissue damage occur due to high cytokine release (including interleukin-1, tumor-necrosis factor alpha, and gamma interferon) and direct cellular toxicity

GVHD occurs in stem cell transplantations as bone marrow graft and also in solid organ transplants. Recogtionin of major histocompatibility antigens (MHC) on immune cells of the recipient is the stimulus that graft competent T cells have for attacking the recipient. Indeed if there is an MHC-mismatch or disparity between donor and receptor instead of an acute transplantation rejection a GVHD occurs.

GVHD may develop despite good genetic compatibility by molecular techniques due to polymorphisms of cytokines including interleukins and growth factors, the presence of differences between the minor histocompatibility antigens and non-MHC encoded gene diversity. Severe GVHD is now rare due to improving histocompatibility techniques, a better T-cell depletion process, in combination with stem cell enrichment. 

Etiology

An acute GVHD starts between 7 to 30 days after either transfusion or transplantation with one of the followings[1]:

  1. Blood product infusion with viable lymphocytes
  2. Maternal-fetal blood transfusion
  3. Intrauterine transfusion
  4. Transfusion of packed red blood cells
  5. Transfusion of frozen cells
  6. Transfusion of platelet and frozen plasma
  7. Transfusion of leukocyte-poor erythrocytes
  8. Therapeutic  whole blood transfusion
  9. Transplantation of fetal thymus
  10. Transplantation of fetal liver and bone marrow

Epidemiology

Data suggest an association between pre-transplant asymmetric dimethylarginine status and early non-relapse mortality in patients with allograft transplantation, both overall and after the onset of acute GVHD. These findings emphasize the relevance of endothelial dysfunction for transplant complications.[2] 

In most of the immunodeficient patients, a GVHD is fatal. Skin is the most commonly affected organ with a typical distribution of rash affecting soles and palms initially, progressing to head, face and body. However, GVHD is a rare disease because of an improvement in tissue matching techniques.

Risk factors for chronic GVHD include acute GVHD (the most critical), MHC mismatch, increasing age, lack of T-cell depletion and donor-receptor gender mismatch.  

Pathophysiology

  1. Donor allograft T cells are causative. It can be demonstrated that acute GVHD may be reduced by T-cell depletion.[3]
  2. GVHD cellular reactions characteristically result from high cytokine production including interleukin-1 (IL-1), tumor necrosis factor alpha (TNF) and gamma interferon (gamma-IFN).
  3. Tissue damage presents due to direct cellular toxicity.
  4. Naive T cells produce cytokines in response to the recipient's APC antigen presentation.
  5. Dysregulation of the immune system and chronic GVHD causes immunosuppression, which leads to hypergammaglobulinemia, autoantibody production and an increased number of CD8+ T-lymphocytes.

Histopathology

Biopsy of active GVHD tissue lesions demonstrates accumulation of mononuclear cells and eosinophils. Besides, infiltration of phagocytic and histiocytic cells are usually present. The infiltrate of mature T cells show increased tissue major histocompatibility complex (MHC) class II expression.

History and Physical

There is a history of a patient known to be immunodeficient (low cellular immunity) and who has had a transfusion of blood or blood products containing potentially immunocompetent cells in the preceding 5 to 30 days.[4][5] The GVHD may appear in 3 distinct forms: hyperacute, acute and chronic.

In the hyperacute the patient may present with a maculopapular lesion, then it progresses to a form resembling that of the toxic epidermal necrolysis, and usually associated with severe diarrhea and death occurs promptly. 

In the acute form of GVHD, the initial manifestation is a maculopapular rash that then becomes diffuse, and if it persists, it may transform in scaly. Other signs and symptoms can present including diarrhea, jaundice, hepatosplenomegaly, tachycardia, pulmonary infiltrates and irritability. The patient presents with a high susceptibility to infections that can cause early death even after the start of the treatment.[6] Diagnosis is usually obviously clinically. It may be confirmed by the presence of filtrate of mature T cells with increased tissue major compatibility complex class II expression. Hyperbilirubinemia and raised alkaline phosphatase are hepatic manifestations. And in some patients, it is a mode of the presentation along with the skin manifestations.

The chronic form may be the result of maternal-fetal transfusion or bone marrow transplantation, and it usually characterizes by chronic desquamation of the skin. Hepatosplenomegaly along with lymphadenopathy may be present. Failure to thrive and chronic diarrhea may be striking. Chronic GVHD has many features in common with collagen vascular disorders and systemic sclerosis.[7] In the oral cavity, chronic GVHD may present as lichen planus with a risk of malignization to oral squamous cell carcinoma that differs from the classical pathology and seems to be more aggressive in patients with stem cell transplantation.[8] Recurrent infections can be a cause of death, and it is often a complication of immunosuppression.[9][10] 

Evaluation

Establishing the diagnosis is by the demonstration of a sex chromosome or HLA chimerism. If chimerism is not initially apparent, incubation of peripheral blood mononuclear cells with interleukin-2 may result in detectable chimerism.

The immunological investigation of a patient with GVHD includes the assessment of lymphocytes, complement system, and phagocytes.[11][12][13]

Quantitative Serum Immunoglobulins

  • IgG
  • IgM
  • IgA
  • IgE

Blood Lymphocyte Subpopulations

  • B lymphocytes (CD19 and CD20)
  • CD4+ T cell count
  • CD8+ T cell count
  • CD4/CD8 ratio

Lymphocyte stimulation assays

  • Phorbol ester and ionophore
  • Phytohemagglutinin
  • Antiserum to CD3

Phagocytic Function  

Nitroblue tetrazolium (NBT) test (before and after stimulation with endotoxin)

  • Unstimulated
  • Stimulated

Neutrophil mobility

  • In medium alone
  • In the presence of chemoattractant

Complement System Evaluation

Measurement of individuals components by immunoprecipitation tests, ELISA, or Western blotting

  • C3 serum levels
  • C4 serum levels
  • CH50 assay

Microbiological studies

  • Blood culture
  • Urine culture
  • Stool culture 
  • Sputum culture
  • Cerebrospinal fluid (culture, chemistry, and histopathology)

Other investigations of immunodeficiency disorders 

  • Complete blood cell count    
  • Bone marrow biopsy
  • Histopathological studies
  • Blood chemistry (including bilirubin and ALP)
  • Tumoral markers
  • Levels of cytokines (granulocyte-colony stimulating factor, IL-1, TNF alpha, and gamma INF)
  • Chest X-ray
  • Diagnostic ultrasound
  • CT scan
  • Fluorescent in situ hybridization (FISH)
  • DNA testing (for most congenital disorders)

Treatment / Management

Prevention of GVHD should take place in any subject suspected of having impaired cell-mediated immunity and which requires the administration of a blood product should receive cells that have been treated with up to 6000 R of radiation to destroy viable lymphocytes and thus prevent GVHD. Whole blood, platelets, lymphocyte-poor erythrocytes, and packed red blood cells must be irradiated.[14] Also, the prevention of acute GVHD is attempted using T-cell depletion and immunosuppression. T-cell depletion is related to higher engraftment failure, but lesser decreased graft-versus-host-tumor effect (antitumor activity was seen after stem-cell transplantation in patients with some hematological malignancies including CML, acute leukemia and multiple myeloma). 

Treatment of acute GVHD includes first-line therapy that is a high dose of steroids (achieved with combinations of methotrexate, ciclosporin, tacrolimus, and mycophenolate mofetil). Then therapy with anti-thymocyte globulin, Campath-1H, anti-CD25 or anti-TNF monoclonal antibodies can be given.[15][16]

Immune system dysregulation and chronic GVHD therapy lead to immunosuppression. The dysregulation can cause the production of autoantibodies, hypo or hyper-gammaglobulinemia and increased CD8+ T cell count.

Treatment of chronic GVHD includes steroids, mycophenolate mofetil, tacrolimus, and ciclosporin as first-line therapy. Second-line therapy includes thalidomide, azathioprine, and monoclonal antibody therapy (e.g., anti-TNF) as a second-line treatment. Response rates to treatment are generally poor. Mortality is 100% if the patient is untreated.[17]

Prochymal and remestemcel-L are a brand name for human mesenchymal stromal cells (MSCs) that are a promising biological therapy for pediatric patients, which are refractory to the conventional steroid treatment of severe acute GVHD.[18]   

Differential Diagnosis

Patients with GVHD on biopsy of the skin or lymph nodes can display a histiocytic infiltration may present, leading to an erroneous diagnosis of Letterer-Siwe disease.[16] Patients with Letterer-Siwe disease have normal immunoglobulin levels and normal T cell immunity, but those with chronic GVHD have hypogammaglobulinemia and deficient T-cell mediated immunity.

Other differential diagnoses

1. Cellular immunodeficiency prompt to GVHD

Interstitial pneumonia in acquired immunodeficient statesRecurrent viral infections in immunodeficiency syndromesChronic mucocutaneous candidiasisPrimary tuberculosis with immunodeficiencyWiskott-Aldrich syndromeSevere combined immunodeficiency diseaseChronic active hepatitisCoccidioidomycosisBehcet diseaseAphthous stomatitis Lymphoid Malignancy Chronic granulomatous diseaseImmunosuppression caused by steroid therapy

2. Bone marrow transplant

RAG-1/RAG-2 SCIDADA-SCID Artemis SCIDX-linked agammaglobulinemiaAcute leukemia

3. Thymus transplant

DiGeorge syndrome

Pertinent Studies and Ongoing Trials

Prochymal is a new drug approved for pediatric patients with acute GVHD refractory to conventional treatment with steroids. In a trial, patients received eight biweekly i.v. Infusions of 2 × 10(6) of human mesenchymal stem cells (hMSCs)/kg for four weeks, with an additional four weekly injections after day twenty-eight for those patients who achieved either an undesired response. Seventy-five patients were treated in this study. Complete and partial response at day twenty-eight was 66.7% for aGVHD grade B, 76.2% for grade C, and 53.3% for grade D. Overall response for individual organs at day twenty-eight was 75.6% for skin, and 44.4% for liver and 58.5% for the gastrointestinal system. The overall reaction at day twenty-eight for patients treated for severe aGVHD was 61.3% and correlated with statistically significant survival at day +100 after Prochymal infusion. The drug infusions were often well tolerated.[19] Despite the favorable risk/benefit profile and safety of this cell product that has been investigated in various  phase I-II studies, several larger and prospective randomized trials are needed to confirm its efficacy in severe refractory acute GVHD and to identify the optimal schedule of administration in terms of cell dose, infusion timing, and pharmacological synergism.[18]

Staging

Acute GVHD is graded from I (mild) to IV (severe). It has profound implications for the management of acute GVHD. Patients grade I respond well to immunotherapy and has a better prognosis. However, severe acute GVHD requires immunosuppression that makes the matter worse, and has a grim prognosis, with high morbidity and mortality rates. 

Prognosis

The prognosis of acute GVHD is poor. Once the disease starts, it leads to a fatal outcome. Very early suspicion of acute GVHD and aggressive therapy with immunosuppressive along with specific monoclonal antibodies can potentially achieve a better result.

Chronic GVHD may evolve:

  1. Directly from acute GVHD, which is known as progressive (has a grim prognosis) 
  2. After a period of resolution, which is known as interrupted (has an intermediate prognosis)  
  3. De novo in a patient with no history of acute GVHD (has a good prognosis)

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.[20]

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

Liver complications include endothelialitis, bile duct destruction, and pericholangitis, but liver biopsy is not done routinely due to associated thrombocytopenia.[21]

Deterrence and Patient Education

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

Skin care: 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.

Diet: Utmost care on choosing what to eat. Better to avoid substances which 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. 

Pearls and Other Issues

  • In an autologous transplant, a disorder mimicking GVHD may occur possibly due to the development of autoreactive T cells, and this should not be understood by autoimmunity. 
  • Acute GVHD is itself immunosuppressive, and infections that have a high rate of morbidity and mortality occur frequently. 

Enhancing Healthcare Team Outcomes

An interprofessional team should educate the parents and manage patients with a likelihood of developing GVHD. Primary care physicians should refer patients known to have T-cell immunodeficiency to a hematologist and a surgeon to prevent infections and other complications. Allogenic stem cell transplantation should occur at a very young age, and bedside specialist should ensure that MHC mismatch between donor and recipient is scanty. The use of allogenic blood products must be irradiated up to 6000 R to prevent acute GVHD. It is vital that the specialist coordinates closely with the patient's family physician to optimize treatment and carry out preventive health services.


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Graft Versus Host Disease - Questions

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Graft versus host reaction is best diagnosed with which method?



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Endomyocardial biopsy is indicated in the workup for which of the following conditions?



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Graft versus host is primarily mediated by what type of cell?



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A patient with a graft-versus-host disease will not have which of the following?



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A 21-year-old male presents to the clinic for a regular follow up. He was treated for acute myeloid leukemia three years ago with chemotherapy, and complete clinical remission was achieved after three courses. Later, however, the patient relapsed within a year, and although he survived, the second remission was challenging to achieve. Which of the following is the best next step in the management of this patient?



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Graft Versus Host Disease - References

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