Basics
Description
- Tissue destruction in allogeneic hematopoietic stem cell transplant (HSCT) recipients is due to donor T cells responding to host antigens.
- 2 types: Acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD); traditionally delineated by time from transplant (aGVHD occurs <100 days, whereas cGVHD occurs ≥100 days). Current designation separates by clinical manifestations.
- Overlap syndrome may occur; that is, "acute-on-chronic"� graft-versus-host disease (GVHD).
- aGVHD: Skin, liver, and gastrointestinal tract (GIT) are most commonly involved.
- cGVHD: may involve any organ; pleomorphic presentation mimicking rheumatologic phenomena
Epidemiology
Incidence
- 25-50% develop aGHVD, depending on disease, conditioning regimen, immunosuppressives, and patient- and donor-specific factors.
- 30-70% develop cGVHD.
Etiology and Pathophysiology
- aGVHD: Antigen-presenting cells are activated by conditioning chemotherapy and/or subsequent infections. This leads to activation of donor T-helper type 1 effector cells causing direct cytotoxicity via released cytokines.
- cGVHD is poorly understood; chronic T-cell activation plays role.
Genetics
Major histocompatibility complex determines degree of host-donor match; greater match leads to decreased aGVHD and cGVHD. �
Risk Factors
- Following associated with greater risk of aGVHD
- Human leukocyte antigen (HLA) discrepancy between host and donor
- Type and remission status of disease
- Conditioning regimen
- Age of recipient
- Sex disparity; highest risk = female donor to male recipient; risk increases for each pregnancy
- ABO blood group incompatibility
- Prophylactic immunosuppressive medications
- Cytomegalovirus (CMV) serostatus disparity
- Risk factors for cGVHD
- Antecedent aGVHD episodes
- HLA disparity
- Use of peripheral blood stem cells
- Sex disparity; highest risk = female donor to male recipient; risk increases for each pregnancy
- Splenectomy
General Prevention
- aGVHD
- Prophylactic immunosuppression with, calcineurin inhibitor plus short-course methotrexate or mycophenolate or sirolimus
- Depletion of host alloantigens
- Depletion of donor T cells
- Emerging role for statins in donor and/or recipient
- cGVHD
- No commonly accepted prophylaxis; limiting flares of aGVHD may minimize cGVHD
Commonly Associated Conditions
- Direct organ injury
- Secondary risks of infection
Diagnosis
History
- GVHD can affect any organ, and comprehensive history should be performed.
- Most common sites of involvement in aGVHD include skin, GI, and hepatic organs.
- Additional sites of involvement in cGVHD include oral, eyes, lungs, and neuromuscular.
- Symptoms are dependent on the organ involved.
- Symptoms of aGVHD may include new skin lesions, anorexia, nausea, vomiting, diarrhea, abdominal pain, GI bleeding, or abdominal cramping.
Physical Exam
- Skin: maculopapular exanthema, lichenoid skin lesions, jaundice
- GI: abdominal tenderness, abnormal bowel sounds, mucosal atrophy/mucositis
- Ocular: photophobia, conjunctivitis, keratoconjunctivitis, episcleritis
- Pulmonary: wheezing from bronchiolitis obliterans
- Musculoskeletal: polymyositis, myasthenia gravis
Differential Diagnosis
- Erythema multiforme
- Gastroenteritis
- Hepatitis
- Mixed connective tissue disease
- Scleroderma
- Sj �gren syndrome
Diagnostic Tests & Interpretation
Initial Tests (lab, imaging)
- CBC
- Liver function studies
- Serum electrolytes
- Hepatic and Doppler sonographies
Follow-up tests & special considerations
- Skin biopsy
- Esophagogastroduodenoscopy (EGD)/colonoscopy
- Liver biopsy
Diagnostic Procedures/Other
- Skin punch biopsy
- In patients with suspicious skin lesions
- EGD and biopsy
- Performed in patients with persistent anorexia and vomiting
- Flexible sigmoidoscopy or colonoscopy with biopsy
- Liver biopsy is risky.
- For patients with isolated transaminitis to suggest hepatic involvement
Test Interpretation
- Cytopenias may result from poor engraftment in cGVHD.
- Elevated alkaline phosphatase (ALP), transaminitis, and bilirubinemia may be a consequence of hepatic involvement.
- Electrolyte derangements and hypoalbuminemia may be evident in patients with GI involvement.
Treatment
General Measures
- aGVHD is graded from I to IV, with IV being most severe.
- cGVHD is graded from 0 to 3, with 3 being most severe.
Medication
First Line
- aGVHD of skin
- Grades I-II: topical triamcinolone 0.1% b.i.d.-t.i.d. to all affected areas but face; hydrocortisone 0.5% on face (adults) and all affected areas (children) (1)[A]
- Grades III-IV: methylprednisolone or prednisone 2 mg/kg/day, tapered slowly over weeks to months (no standard taper exists) plus calcineurin inhibitor titrated to optimal dose by therapeutic drug monitoring (1)[A]
- Topical corticosteroids may be administered concomitantly with systemic corticosteroids.
- aGVHD of GIT
- Grade I: enteric-coated budesonide 6-9 mg daily in divided doses and/or beclomethasone corn oil emulsion 2 mg q.i.d. (1)[A]
- Grades II-IV: methylprednisolone or prednisone 2 mg/kg/day, tapered slowly over weeks to months (no standard taper exists) plus calcineurin inhibitor titrated to optimal dose by therapeutic drug monitoring (1)[A]
- Enteric-coated budesonide and/or beclomethasone corn oil emulsion 2 mg q.i.d. may be used concomitantly (1)[A].
- aGVHD of liver and atypical presentations
- Grades I-IV: methylprednisolone or prednisone 2 mg/kg/day, tapered slowly over weeks to months (no standard taper exists) plus calcineurin inhibitor titrated to optimal dose by therapeutic drug monitoring (1)[A].
- cGVHD
- Prednisone 1 mg/kg/day; no standard taper schedule (2)[A]
- Additional treatment should be tailored to specific organ(s) involved (2)[C].
Second Line
- Second-line therapy of aGVHD is often termed "steroid-refractory GVHD"�; despite nomenclature, high-dose corticosteroids continue concomitantly with second-line therapy of aGVHD.
- Failure of first-line corticosteroids determined at days 5-7 of treatment for aGVHD.
- Second-line therapy for aGVHD is mycophenolate mofetil 15 mg/kg PO/IV b.i.d. in those who have not received mycophenolate mofetil (1)[A].
- Preferred second-line therapy for cGVHD is not known (2)[B].
- Corticosteroids used concomitantly with those listed in the following text.
- aGVHD of skin
- Equine antithymocyte globulin 40 mg/kg/day IV � 4 days (1),(3)[C]
- Denileukin diftitox 9 μg/kg IV on days 1, 3, 5, 15, 17, and 19 (3)[C]
- Extracorporeal photopheresis (3)[C]
- Pentostatin 1.4 mg/m2/day IV � 3 days q14 days (1)[C]
- Sirolimus 3-4 mg/day orally titrated to serum level 3-12 ng/mL(1),(3)[C]
- Topical tacrolimus 0.03-0.1% ung or pimecrolimus 1% cream b.i.d. (1),(3)[C]
- aGVHD of GIT
- Alemtuzumab 10-30 mg IV daily for 3-5 days(1),(3)[C]
- Equine antithymocyte globulin 40 mg/kg/day IV � 4 days (1),(3)[C]
- Denileukin diftitox 9 μg/kg IV on days 1, 3, 5, 15, 17, and 19 (3)[C]
- Etanercept 0.4 mg/kg SQ twice weekly � 8 weeks (max: 25 mg total) (1),(3)[C]
- Infliximab 10 mg/kg IV weekly � 4 weeks (GVHD grades I-II) (1),(3)[C]
- Pentostatin 1.4 mg/m2/day IV � 3 days q14 days (1)[C]
- Sirolimus 3-4 mg/day orally titrated to serum level 3-12 ng/mL(1),(3)[C]
- aGVHD of liver
- Alemtuzumab 10-30 mg IV daily for 3-5 days(1),(3)[C]
- Equine antithymocyte globulin 40 mg/kg/day IV � 4 days (1),(3)[C]
- Denileukin diftitox 9 μg/kg IV on days 1, 3, 5, 15, 17, and 19 (3)[C]
- Extracorporeal photopheresis (1),(3)[C]
- Pentostatin 1.4 mg/m2/day IV � 3 days q14 days or 1.5 mg/m2/day IV on days 1-3 and 15-17 (1),(3)[C]
- Sirolimus 3-4 mg/day orally titrated to serum level 3-12 ng/mL(1),(3)[C]
- cGVHD
- Etanercept 0.4 mg/kg SQ twice weekly � 8 weeks (max: 25 mg total dose) (1),(3)[C]
- Extracorporeal photopheresis (1),(3)[C]
- Mycophenolate mofetil 15 mg/kg PO/IV b.i.d. (1),(3)[C]
- Topical tacrolimus 0.03-0.1% ointment or pimecrolimus 1% cream b.i.d. (1),(3)[C]
- Triamcinolone 0.1% (all but face) and hydrocortisone 0.5% b.i.d.-t.i.d. (1),(3)[C]
Issues for Referral
Specialists to help manage organ-specific management of cGVHD �
Additional Therapies
- Limiting sun exposure (1)[B]
- Bowel rest (1)[A]
- Total parenteral nutrition (1)[A]
- Anti-infectives, including antibacterial, antiviral, antifungal, and antipneumocystis agents (1)[A]
- Physical therapy
- Pain management
- Vaccinations (once GVHD resolves and immunosuppression ends)
Surgery/Other Procedures
Not indicated �
Complementary & Alternative Therapies
None recommended �
Inpatient Considerations
Admission Criteria/Initial Stabilization
- GI antispasmodics after excluding infection
- IV fluids to prevent dehydration
- May consider total parenteral nutrition if severe malabsorption.
- Treat infections with anti-infective agents
- Wound care for high-grade skin lesions
IV Fluids
IV fluids with electrolyte replacement for patients presenting with electrolyte dyscrasias �
Nursing
No specific nursing instructions, except for close symptom monitoring and routine nursing care. �
Discharge Criteria
Safe discharge requires resolution of presenting symptoms and provisions for adequate follow-up. �
Ongoing Care
Follow-up Recommendations
Patients should continue to follow-up with their transplant physician, consulting physicians, and supportive care staff. �
Patient Monitoring
- Nutritional status, including oral fluid intake
- Use of long-term corticosteroids requires blood pressure, glucose, and osteoporosis screening.
Pediatric Considerations
Developmental assessment every 6-12 months �
Diet
- Increase oral intake once diarrhea <500mL/day
- Lactose-free diet
- High-protein diet ≥1.5 g/kg/day) to offset catabolic effect of medications and disease
- No role for neutropenic or low-bacteria diet
Patient Education
- Avoidance of excessive exposure to the sun
- Patients should avoid sedentary lifestyle and exercise regularly while on corticosteroids.
- Patients should minimize infectious risks while on immunosuppressive medications.
Prognosis
- The response and overall grade of aGVHD correlates with outcome.
- Patients with complete response have 22% mortality rate compared to 75% mortality rate in nonresponders (4).
- Extensive disease, progressive onset, thrombocytopenia, HLA-nonidentical marrow donors, and failure to taper steroids for aGVHD before the onset of progressive cGVHD correlate with high mortality.
Complications
- Infectious complications
- Invasive fungal infections
- Pneumocystis jiroveci pneumonia
- Herpesvirus infection
- CMV infection
- Proximal muscle wasting
- Organ failure and graft rejection
References
1.Martin �PJ, Rizzo �JD, Wingard �JR, et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2012;18(8):1150-1163. �
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2.Dignan �FL, Scarisbrick �JJ, Cornish �J, et al. Organ-specific management and supportive care in chronic graft-versus-host disease. Br J Haematol. 2012;158(1):62-78. �
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3.Pidala �J, Anasetti �C. Glucocorticoid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2010;16(11):1504-1518. �
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4.Deeg �HJ, Henslee-Downey �PJ. Management of acute graft-versus-host disease. Bone Marrow Transplant. 1990;6(1):1-8. �
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Codes
ICD09
- 279.50 Graft-versus-host disease, unspecified
- 279.51 Acute graft-versus-host disease
- 279.52 Chronic graft-versus-host disease
- 279.53 Acute on chronic graft-versus-host disease
- 996.80 Complications of transplanted organ, unspecified
ICD10
- D89.813 Graft-versus-host disease, unspecified
- D89.810 Acute graft-versus-host disease
- D89.811 Chronic graft-versus-host disease
- D89.812 Acute on chronic graft-versus-host disease
SNOMED
- 234646005 Graft-versus-host disease (disorder)
- 402355000 Acute graft-versus-host disease
- 402356004 Chronic graft-versus-host disease
- 47650006 Graft versus host reaction (finding)
Clinical Pearls
- Acute GVHD develops within 100 days after allogeneic hematopoietic-cell transplantation.
- Most common sites involved in aGVHD include skin, GI, and liver.
- Rate of response and depth of involvement correlate with outcome in patients with GVHD.