Question 25

College answer

A detailed knowledge on GVHD was lacking for many candidates, and many candidates did not recognise GVHD as different from graft failure/graft rejection. Many candidates could not outline the different clinical pictures in acute vs chronic GVHD. Whilst most candidate mentioned skin/liver/GIT involvement, very few
candidates recognised bronchiolitis obliterans and neuromyopathy as part of the clinical picture of chronic GVHD. Poorer answers in evaluation did not include the need for the differential diagnosis of sepsis to be excluded, and the rationale for diagnostic evaluation was commonly omitted.

Discussion

As about 85% of the large ICUs around Australia NZ and Hong Kong do not have bone marrow transplant services, it is in fact surprising that a detailed knowledge on GVHD was not lacking for even more of the candidates. That 25% had passed is remarkable. 

a) Pathogenesis of GVHD, in under two minutes:

1. Proinflammatory stimuli (eg. radiation, chemotherapy, leukaemia itself)
2. Activation of host antigen presenting cells
3. Presentation of alloantigens to donated T lymphocytes
4. Activation and proliferation of donor T cells
5. Direct cytotoxic and indirect inflammatory organ damage

b) Risk factors for GVHD:

• Unrelated donors
• HLA mismatching
• Donor/recipient sex mismatch (female to male is greatest risk)
• Racial mismatch
• Older age (over 40)
• Aggressive conditioning
• Total body irradiation
• High CD34⁺ cell dose
• Blood cell grafts (as opposed to bone marrow)
• CMV positive status
• Functional status (Karnofsky performance score less than 90)

c) Clinical presentation of GVHD:

• Acute:  within 100 days of HSCT, and classical features:
  • Skin: inflammatory erythematous mculopapular rash
  • Gastrointestinal: nausea, vomiting, diarrhoea, anorexia, mucositis
  • Liver: elevated bilirubin
• Late onset acute: same clinical features, but after 100 days
• Chronic: onset at any time, but with chronic features:
  • Absence of acute features (skin, gastrointestinal or liver)
  • Sclerotic skin disease with hyperpigmentation and ichthyosis
  • Lichenoid oral and genital mucosa
  • Gingival disease, oral pseudomembranes
  • Oesophageal strictures
  • Nail changes (dystrophy, ridging, etc)
  • Alopecia
  • Ocular changes (chronic conjunctivitis)
  • Myosits 
  • Bronchiolitis obliterans
  • Myositis and neuromyopathy
  • Pleural and pericardial effusions

d) Diagnostic evaluation

• Histological confirmation is the gold standard (the affected organ is biopsied, to discriminate between organ-specific differentials, eg. where CMV colitis is an equally likely explanation for the diarrhoea)
• Clinical criteria (especially when it comes to the diagnosis of chronic GVHD)
• Biomarkers are mainly experimental/investigational
• Proteomic analysis of plasma or urine polypeptides (according to UpToDate, IL-2 receptor-alpha, tumor necrosis factor receptor-1, interleukin-8, and hepatocyte growth factor)
• Flow cytometry looking for activated (CD30 positive) CD8+ T cells