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Graft-versus-Host Disease (GVHD): Causes, Symptoms, and Management

Understanding Graft-versus-Host Disease

Graft-versus-Host Disease (GVHD) is a potentially fatal complication of allogeneic hematopoietic stem cell transplant (HSCT) where donor T-cells attack recipient tissues. It remains the major barrier to transplant success.

Pathophysiology

Donor T-cells recognize recipient HLA/miHA disparities → activation, proliferation, cytokine storm (TNF-α, IFN-γ, IL-1, IL-6) → tissue damage. Two clinical forms exist:

Acute GVHD (aGVHD)

  • Typically <100 days post-transplant (but "late acute" >100 days recognized)
  • Classic triad: Skin (maculopapular rash → bullae/desquamation), GI (nausea, vomiting, secretory diarrhea, ileus, bleeding), Liver (cholestatic jaundice, elevated bilirubin/ALP)
  • Graded 1–4 (MAGIC/Glucksberg); overall grade guides therapy

Chronic GVHD (cGVHD)

  • Typically >100 days; overlap syndrome exists
  • Scleroderma-like fibrosis, sicca syndrome, bronchiolitis obliterans, fasciitis, esophageal strictures, ocular/genital involvement
  • NIH consensus criteria: diagnostic, distinctive, common features; organ scoring

Risk Factors

  • HLA mismatch (especially haploidentical, mismatched unrelated)
  • Older donor/recipient age
  • Female donor → male recipient (H-Y antigens)
  • Peripheral blood stem cells > bone marrow > cord blood
  • Prior acute GVHD
  • Reduced-intensity conditioning (↑cGVHD risk)

Prevention Strategies

  • HLA matching (8/8 or 10/10 ideal)
  • Graft manipulation: T-cell depletion (ex vivo or in vivo with post-transplant cyclophosphamide/PTCy)
  • PTCy revolutionized haploidentical transplant—now standard for many platforms
  • Calcineurin inhibitor (tacrolimus) + mycophenolate/MTX prophylaxis
  • Abatacept, sirolimus, bortezomib in clinical trials

Treatment

  • aGVHD: High-dose steroids (methylprednisolone 2 mg/kg/day) first-line. Steroid-refractory: ruxolitinib (FDA-approved), ibrutinib, ECP, anti-thymocyte globulin, infliximab, vedolizumab (GI), mesenchymal stromal cells.
  • cGVHD: Steroids ± calcineurin inhibitor first-line. FDA-approved: ibrutinib, ruxolitinib, belumosudil (ROCK2 inhibitor). ECP, imatinib, low-dose IL-2, photopheresis.
  • Supportive care: Infection prophylaxis (PJP, HSV, VZV, fungal), nutrition, PT/OT, ocular/oral care, pulmonary rehab.

Prognosis and Survivorship

Severe GVHD increases non-relapse mortality. Chronic GVHD affects 30–70% of long-term survivors, driving quality-of-life impairment. Multidisciplinary survivorship clinics are essential. Novel agents (JAK/ROCK inhibition) are transforming outcomes.

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