Categories
Internal Medicine

Graft-versus-host disease (GvHD)

Introduction

Graft-versus-host disease (GvHD) is a medical complication following the receipt of transplanted tissue from a genetically different person.

  • Type IV hypersensitivity reactino

Billingham Criteria:

3 criteria must be met in order for GvHD to occur.

  1. An immuno-competent graft is administered, with viable and functional immune cells.
  2. The recipient is immunologically different from the donor – histo-incompatible.
  3. The recipient is immuno-compromised and therefore cannot destroy or inactivate the transplanted cells.

Classification

Acute GvHD:

  • Classic acute GvHD (onset ≤ 100 days)
  • Persistent/recurrent/late-onset GvHD (onset > 100 days)

Chronic GvHD:

Pleiotropic, multiorgan syndrome involving tissue inflammation and fibrosis that often results in permanent organ dysfunction. Chronic GVHD is fundamentally caused by replacement of the host’s immune system with donor cells, although the heterogeneity of clinical manifestations suggests that patient, donor, and transplant factors modulate the phenotype.

  • Classic chronic GvHD (occurs at any time)
  • Overlap syndrome (occurs at any time)
    • Features of both acute & chronic GvHD
blood686642f1
Acute, late acute, chronic overlap, and classic chronic GVHD. The box sizes do not reflect prevalence. | Lee S. J. (2017). Classification systems for chronic graft-versus-host disease. Blood, 129(1), 30–37. doi:10.1182/blood-2016-07-686642

Aetiology

  • Transfusion-associated GvHD
    • Associated with transfusion of un-irradiated blood to immunocompromised recipient or in situations in which the blood donor is homozygous and the recipient is heterozygous for an HLA haplotype
  • Thymus transplantation
    • Recipient’s thymocytes would use the donor thymus cells as models when going through the negative selection to recognize self-antigens, and could therefore still mistake own structures in the rest of the body for being non-self
  • Thymoma-associated multiorgan autoimmunity (TAMA)
    • Patient’s own malignant thymus produces self-directed T cells (as it is incapable of appropriately educating developing thymocytes to eliminate self-reactive T cells)

Pathophysiology

3 phases:

  1. Activation of APC (antigen-presenting cells)
  2. Activation, proliferation, differentiation and migration of effector cells
  3. Target tissue destruction
nihms-115970-f0003
GVHD Pathophysiology: In Phase I, the recipient conditioning regimen damages host tissues and causes release of inflammatory cytokines such as TNFα, IL-1 and IL-6. Increased levels of these cytokines leads to activation of host antigen presenting cells (APCs). In Phase II, host APCs activate mature donor cells. The subsequent proliferation and differentiation of these activated T cells produces additional effectors that mediate the tissue damage, including Cytotoxic T Lymphocytes, Natural Killer (NK) cells, TNFα and IL-1. Lipopolysaccharide (LPS) that has leaked through the damaged intestinal mucosa triggers additional TNFα production. TNFα can damage tissue directly by inducing necrosis and apoptosis in the skin and GI tract through either TNF receptors or the Fas pathway. TNFα plays a direct role in intestinal GVHD damage which further amplifies damage in the skin, liver and lung in a “cytokine storm.” | Ferrara, J. L. M., Levine, J. E., Reddy, P., & Holler, E. (2009). Graft-versus-host disease. Lancet (London, England), 373(9674), 1550–1561. https://doi.org/10.1016/S0140-6736(09)60237-3
transfusion-associated-graft-versus-host-disease-signs-and-symptoms
The Calgary Guide | http://calgaryguide.ucalgary.ca/

Clinical features

Acute GvHD:

  • Skin (M/C affected organ): Maculopapular skin rash
  • Upper GIT: Nausea and/or anorexia + positive histology
  • Lower GIT: Watery diarrhoea ≥ 500ml +/- severe abdominal pain +/- bloody diarrhoea or ileus (after exclusion of infectious aetiology)
  • Liver: Cholestatic hyperbilirubinemia
mi2018-9451950.004
A patient presents with aGVHD after early GVHD prophylaxis withdrawal. Palmar (top) and plantar (bottom right) erythema and bullae formations are typical skin manifestations of aGVHD. The erythema of the face spreads to the neck, chest, and shoulders often resulting into generalized erythroderma. aGVHD manifestation in the oral cavity involves stomatitis and cheilitis (bottom left). The face shows signs of cushingoid features resulting from adverse side effects of corticosteroids. | Kuba, A., & Raida, L. (2018). Graft versus Host Disease: From Basic Pathogenic Principles to DNA Damage Response and Cellular Senescence. Mediators of inflammation, 2018, 9451950. doi:10.1155/2018/9451950

Chronic GvHD:

  • Skin: Dyspigmentation, new onset alopecia, poikiloderma, lichen planus-like eruptions or sclerotic features
  • Nails: Nail dystrophy or loss
  • Mouth: Xerostomia, ulcers, lichen-type features, restrictions of mouth opening from sclerosis
  • Eyes: Dry eyes, sicca syndrome, cicatricial conjunctivitis
  • Muscles, fascia, joints: Fasciitis, myositis, or joint stiffness from contractures
  • Female genitalia: Vaginal sclerosis, ulcerations
  • GI tract: Anorexia, weight loss, esophageal web or strictures
  • Liver: Jaundice, transaminitis
  • Lungs: Restrictive or obstructive defects on pulmonary function tests, bronchiolitis obliterans, pleural effusions
  • Kidneys: Nephrotic syndrome (rare)
  • Heart: Pericarditis
  • Marrow: Thrombocytopenia, anemia, neutropenia
blood686642f2
Diagnostic skin and mouth manifestations. (A) Lichen planus and poikiloderma. (B) Fasciitis and sclerosis. (C) Sclerosis. (D) Oral lichen planus. | Lee S. J. (2017). Classification systems for chronic graft-versus-host disease. Blood, 129(1), 30–37. doi:10.1182/blood-2016-07-686642

Classical features:

  • Selective damage to the liver, skin (rash), mucosa, and the gastrointestinal tract:
    • GI GvHD:  intestinal inflammation, sloughing of the mucosal membrane, severe diarrhea, abdominal pain, nausea, and vomiting
    • Skin GvHD: Diffuse red maculopapular rash, sometimes in a lacy pattern

Management

Treatment:

  • IV glucocorticoids: Prednisone
  • Calcineurin inhibitors: Cyclosporine & tacrolimus

Prophylaxis:

  • Methotrexate, cyclosporin and tacrolimus

Leave a Reply

%d bloggers like this: