Graft versus host disease
Description
- Donor T cells recognise host tissue as foreign after allogeneic HSCT (or, rarely, transfusion)
- Billingham requirements - all three needed:
- Graft contains immunocompetent cells
- Host expresses antigens absent from the donor
- Host cannot reject the graft
Acute vs chronic - classified by features, not by day 100
| Acute | Chronic | |
|---|---|---|
| Target organs | Skin, gut, liver | Multi-system, autoimmune-like |
| Pathology | Apoptosis, epithelial destruction | Fibrosis, sclerosis |
| Typical onset | Around engraftment to day 100 | 3-24 months |
| Categories | Classic; late-onset acute (>day 100) | Classic; overlap syndrome (features of both) |
- *The day-100 rule is obsolete* (NIH consensus) - a patient with new sclerosis at day 60 has chronic GVHD
- Graft-versus-leukaemia is the same biology - abolishing GVHD entirely raises relapse
Epidemiology
- Acute GVHD grade II-IV: ~30-50% of allografts (lower with post-transplant cyclophosphamide)
- Chronic GVHD: ~30-50%; the leading cause of late non-relapse mortality and of poor quality of life in survivors
- Chronic GVHD organ involvement: skin ~67%, mouth ~60%, liver ~52%, lung ~50%, eyes ~48%, joints/fascia ~48%, GI ~30%, genital ~12%
- Transfusion-associated GVHD: rare, mortality >90%
Aetiopathogenesis
Three phases (acute)
1. Conditioning-induced tissue injury -> cytokine storm (TNF, IL-1), DAMPs/PAMPs from a damaged gut barrier, upregulated host MHC
2. Donor T cell activation by host APCs -> Th1/Th17 polarisation, clonal expansion
3. Effector phase - CTL, NK, TNF/IFN-gamma -> apoptosis of crypt and basal keratinocytes
- Minor histocompatibility antigens drive GVHD even in a fully HLA-matched sibling transplant
Chronic
- Thymic damage -> failure of negative selection -> autoreactive T cells escape
- B cell activation (BAFF excess), autoantibody, germinal centre reactions
- TGF-beta/ROCK2-driven fibrosis - the target of belumosudil
Risk factors
| Acute | Chronic |
|---|---|
| HLA disparity (mismatch, unrelated) | Higher HLA mismatch |
| Female donor -> male recipient (H-Y antigens) | Same, plus donor alloimmunisation (prior pregnancy/transfusion) |
| Myeloablative conditioning intensity | Older donor and recipient age |
| Peripheral blood > marrow > cord stem cell source | Peripheral blood source |
| GVHD prophylaxis regimen | Prior acute GVHD (strongest) |
| CMV seropositivity | Unirradiated donor lymphocyte infusion, prior splenectomy, donor EBV seropositivity |
Transfusion-associated GVHD
- Viable donor T lymphocytes engraft in a recipient who cannot reject them
- Three drivers: degree of recipient immunodeficiency, number of viable donor T cells (blood age, leucodepletion, irradiation), and degree of HLA similarity
- *Paradox: the risk is highest with blood from a first-degree relative or an HLA-matched donor* - a shared haplotype means the host does not see the graft as foreign
- Also occurs in immunocompetent recipients for this reason
Diagnosis
Acute - the classic triad
- Dermatitis + hepatitis + enteritis
- Skin first and commonest - around neutrophil engraftment
- Pruritic/painful maculopapular rash: nape of neck, ears, palms and soles, then generalises
- Severe: bullae, desquamation - resembles toxic epidermal necrolysis
- Gut - secretory, green, high-volume diarrhoea; cramping, bleeding, ileus (lower); anorexia, nausea, vomiting, dyspepsia (upper)
- Liver - cholestatic, inc bilirubin and ALP; encephalopathic liver failure is unusual, and liver/gut usually follow skin
- Biopsy supports but does not exclude; *never delay treatment for histology*
Acute organ staging
| Stage | Skin | Liver (bilirubin) | Gut (diarrhoea) |
|---|---|---|---|
| 1 | Rash <25% BSA | 20-30 micromol/L | >500 mL/day (>30 mL/kg) |
| 2 | 25-50% | 31-60 | >1000 mL/day (>60 mL/kg) |
| 3 | Generalised erythroderma | 61-150 | >1500 mL/day (>90 mL/kg) |
| 4 | Erythroderma + bullae/desquamation | >150 | Severe pain or ileus |
- Overall grade I-IV (Glucksberg/MAGIC) from the combination
- Grade I = skin only -> topical therapy alone
- Grade II-IV -> systemic therapy
- MAGIC biomarker algorithm (ST2 + REG3alpha) predicts steroid-refractoriness and non-relapse mortality
Chronic - resembles a connective tissue disease
- Skin: lichen planus-like papules -> sclerosis/morphoea, dyspigmentation, telangiectasia, fasciitis, contracture
- Mouth: lichenoid change, sicca, ulceration, scalloped tongue, restricted opening
- Eyes: keratoconjunctivitis sicca, cicatricial conjunctivitis
- Lung: bronchiolitis obliterans (diagnostic on its own) - obstructive spirometry, air trapping on expiratory CT, dyspnoea, pneumothorax
- GI/liver: oesophageal web or stricture, malabsorption, cholestasis, cirrhosis
- Joints/fascia: contracture, myositis; genital: stenosis, phimosis
- Refractory thrombocytopenia and functional asplenia - adverse markers
- NIH consensus: score 8 organs 0-3 -> mild / moderate / severe
Differential
- Drug eruption, viral (CMV, adenovirus, HHV-6), Clostridioides difficile, neutropenic enterocolitis
- Sinusoidal obstruction syndrome for the liver: Seattle triad - hepatomegaly, weight gain, hyperbilirubinaemia (+ RUQ pain, reversed portal flow); timing is earlier, before engraftment
- Engraftment syndrome
Transfusion-associated GVHD
- 1-2 weeks post-transfusion: fever, rash, diarrhoea, deranged LFTs -> profound pancytopenia from marrow aplasia
- The marrow is host tissue, so unlike post-HSCT GVHD it is destroyed - hence the >90% mortality
Management
A. Prophylaxis - the highest-yield intervention
- Post-transplant cyclophosphamide (day +3 and +4) + tacrolimus + MMF is now standard, including matched donors
- Alloreactive T cells are proliferating at day 3 and are preferentially killed; regulatory T cells (high aldehyde dehydrogenase) are spared
- BMT CTN 1703: less severe acute and chronic GVHD, higher immunosuppression-free survival
- Made haploidentical transplantation feasible
- Older backbone: calcineurin inhibitor (ciclosporin/tacrolimus) + methotrexate (mucositis, delayed engraftment) or MMF
- In vivo T-cell depletion - ATG or alemtuzumab (anti-CD52): unrelated/mismatched donors only
- *Reduces GVHD but also graft-versus-leukaemia -> higher relapse and infection*
- Abatacept for mismatched unrelated donors
B. Acute GVHD
- Grade I (skin only): topical corticosteroid, continue prophylaxis
- Grade II-IV: prednisolone/methylprednisolone 1-2 mg/kg/day + continue calcineurin inhibitor
- Non-absorbable oral budesonide/beclomethasone for isolated upper GI disease
- Assess response at day 5-7; taper slowly over weeks once responding
- Steroid-refractory: ruxolitinib is first-line (REACH2 - superior response to best available therapy)
- Superseded the old menu of ATG, MMF, pentostatin, infliximab
- Watch cytopenias, CMV reactivation
- Extracorporeal photopheresis, mesenchymal stromal cells, alpha-1 antitrypsin, vedolizumab - later options
- Gut rest, TPN, octreotide, transfusion support
C. Chronic GVHD
- Mild/localised: topical therapy alone (steroid, tacrolimus ointment, ciclosporin drops, dexamethasone mouthwash)
- Moderate-severe: prednisolone ~1 mg/kg +/- calcineurin inhibitor, then taper to alternate-day
- Steroid-refractory or steroid-dependent - three approved targeted agents
- Ruxolitinib (JAK1/2) - REACH3, best evidence, usually first
- Belumosudil (ROCK2) - antifibrotic, good in sclerotic and lung disease
- Ibrutinib (BTK) - B-cell driven disease
- Also: extracorporeal photopheresis (skin, oral, hepatic), MMF, sirolimus, rituximab, low-dose IL-2
- Bronchiolitis obliterans: FAM - inhaled Fluticasone + Azithromycin + Montelukast, plus systemic therapy
- Ancillary care is not optional: physiotherapy for contractures, ocular lubricants/scleral lenses, dental, dermatology, vaginal dilators, bone protection
D. Supportive care in anyone on GVHD therapy
- Functionally asplenic and profoundly immunosuppressed
- PJP prophylaxis, antifungal (mould-active if steroid-treated), antiviral
- CMV monitoring and pre-emptive therapy; valganciclovir myelosuppression is the limiting problem in a D-/R+ pair - letermovir prophylaxis
- Encapsulated organism prophylaxis, revaccination programme, IVIG if hypogammaglobulinaemic
- Corticosteroid complications: bone, glucose, myopathy, cataract
E. Transfusion-associated GVHD
- Prevention only - treatment is futile
- Gamma-irradiate cellular blood components for: HSCT recipients, Hodgkin lymphoma, purine analogue/alemtuzumab/ATG exposure, congenital T-cell immunodeficiency, intrauterine and neonatal exchange transfusion, and any directed donation from a relative
- Leucodepletion alone is NOT sufficient
Associations
- Graft-versus-leukaemia effect - inseparable from GVHD; chronic GVHD associates with lower relapse
- Donor lymphocyte infusion - induces both
- CMV, EBV (PTLD), adenovirus, HHV-6 reactivation
- Sinusoidal obstruction syndrome, engraftment syndrome, idiopathic pneumonia syndrome
- Transplant-associated thrombotic microangiopathy (calcineurin inhibitors, sirolimus)
- Secondary malignancy - squamous cell carcinoma of skin and oral mucosa in chronic GVHD
- Therapy-related AML/MDS ~1% after autologous transplant
- Autoimmune cytopenias, hypothyroidism, adrenal insufficiency
Natural history & complications
- Response to first-line steroid in acute GVHD ~50%; steroid-refractory disease carries the bulk of the mortality
- Acute grade III-IV: non-relapse mortality >50%
- Chronic GVHD: median duration of systemic therapy 2-3 years; ~50% still on immunosuppression at 5 years
Adverse prognostic features
- Acute: grade III-IV, gut and liver involvement, steroid refractoriness, high MAGIC biomarker (ST2/REG3alpha)
- Chronic: progressive onset (acute -> chronic without an interval), thrombocytopenia <100, extensive skin sclerosis, bronchiolitis obliterans, hyperbilirubinaemia, poor performance status
Causes of death
- Infection (the immunosuppression, not the GVHD itself), organ failure, relapse
- Bronchiolitis obliterans - largely irreversible; a lung transplant indication in survivors
- Long-term survivors need lifelong survivorship care: skin cancer surveillance, bone density, endocrine, cardiovascular, fertility, psychosocial
🔒
6 more sections, plus exam facts
Premium unlocks every note across every specialty, and the full exam fact library behind it.
Get premium access