Basics
Description
Graft-versus-host disease (GVHD) is a multiorgan inflammatory process that develops when immunologically competent T lymphocytes from a histoincompatible donor are infused into an immunocompromised host unable to reject them. Divided into acute and chronic, historically based on time of presentation but best delineated by clinicopathologic findings.
- Acute: develops within 100 days after allogeneic hematopoietic stem cell transplant (HSCT); affects skin, GI tract, and/or liver
- Chronic: develops 100 days after allogeneic HSCT; presents with diverse features resembling autoimmune syndromes
- Chronic subtypes
- Progressive: extension of acute GVHD
- Quiescent: after resolution of acute GVHD
- De novo: no prior acute GVHD
Epidemiology
- Acute GVHD (grades II-IV): 10-80% of patients receiving T-cell-replete HSCT
- 35-45% for human leukocyte antigen (HLA)-identical related donor bone marrow
- 60-80% if 1-antigen HLA-mismatched unrelated donor bone marrow or peripheral stem cells
- 35-65% if 2-antigen HLA-mismatched unrelated umbilical cord blood
- Chronic GVHD: most common cause of late morbidity and mortality of allogeneic HSCT
- 15-25% if HLA-identical related marrow
- 40-60% if HLA-matched unrelated marrow
- 54-70% if HLA-matched unrelated peripheral stem cells
- 20% if unrelated umbilical cord blood
- Flare-ups triggered by infection (usually viral)
Risk Factors
- HLA disparity (both major and minor antigens)
- Older donor or recipient age
- Stem cell source and dose
- Highest risk: with peripheral stem cells
- Lowest risk: with umbilical cord blood
- Donor leukocyte infusions
- Reactivation of viruses (e.g., HHV-6, CMV)
- T-cell depletion decreases incidence.
- Acute GVHD-specific
- Higher intensity conditioning regimen
- Prior pregnancies in female donors
- Gender mismatch
- Chronic GVHD specific
- Severity of acute GVHD
- Malignancy as indication for transplantation
- Use of total-body irradiation
- Type of immunosuppressive prophylaxis
Genetics
- HLA gene complex on chromosome 6; inherited as haplotype
- Full siblings: 25% chance HLA identical
- Minor histocompatibility antigen differences likely account for GVHD in HLA-identical sibling stem cell transplants.
General Prevention
- Transfusion: irradiation of all cellular blood products for patients at risk
- Stem cell transplantation
- Selection of a histocompatible donor
- Immunosuppression (gold standard): cyclosporine or tacrolimus with a short course of methotrexate
- Other options: corticosteroids, sirolimus, mycophenolate mofetil, and low-dose cyclophosphamide
- Donor T-cell depletion with anti-T-cell antibodies ex vivo in graft or in vivo in recipient
Pathophysiology
- Acute GVHD: interaction of donor and host innate and adaptive immune responses
- Severity related to degree of HLA mismatch
- 3 phases ending in "cytokine storm"
- Tissue damage by conditioning regimen
- Priming and activation of donor T cells
- Infiltration of activated T cells into skin, GI tract, and liver resulting in apoptosis
- Chronic GVHD: findings similar to autoimmune disorders: donor T cells directed against host antigens, donor T-cell autoreactivity, B-cell dysregulation, regulatory T-cell deficiency; marked collagen deposition in target organs and lack of T-cell infiltration
Etiology
- Hematopoietic stem cell transplantation
- Transfusion of nonirradiated blood products to immunodeficient hosts: caused by viable donor lymphocytes engrafting in the recipient
- Transfusion of nonirradiated blood from a donor homozygous for 1 of the recipient's HLA haplotypes (1st- or 2nd-degree relative)
- Intrauterine maternal-fetal transfusions and exchange transfusions in neonates
- Solid organ grafts: contain immunocompetent T cells, into immunosuppressed recipient
Diagnosis
History
- Acute GVHD
- Rash: usually 1st manifestation; pruritus or burning sensation can precede rash.
- Diarrhea, abdominal pain, and intestinal bleeding: unusual to precede skin disease
- Anorexia, nausea, vomiting, and dyspepsia
- Jaundice (liver involvement)
- Chronic GVHD
- Dry eyes and/or dry mouth, blurry vision, eye irritation, photophobia, eye pain
- Difficulty swallowing or retrosternal pain
- Sensitivity to mint, spicy foods, or tomatoes
- Weight loss, failure to thrive, anorexia, nausea, vomiting, diarrhea
- Dyspnea, wheezing, cough
- Poor wound healing, especially post trauma
- Joint stiffness, muscle cramps
- Infections: pneumococcal sepsis, Pneumocystis jiroveci, fungal infections
Physical Exam
- Acute/transfusion-associated GVHD
- Skin (most common site)
- Maculopapular rash of palms, soles; can become confluent erythroderma
- Severe form: bullae formation, to even full-thickness necrosis
- GI tract: weight loss; profuse, watery, often green, and often bloody diarrhea
- Liver: jaundice; atypical findings: painful hepatomegaly, ascites, rapid weight gain
- Chronic GVHD
- Skin (involved in almost every patient)
- Hyper- or hypopigmentation, xerosis (skin dryness), pruritus, scaling, patchy erythema, poikiloderma, skin atrophy; lichenoid, eczematous, and/or sclerodermatous changes
- Advanced scleroderma: thickened, tight, and fragile skin
- Hair: thin, fragile; premature graying
- Scalp: dry or seborrheic
- Nails: dystrophic, fragile; entire nail loss
- Mouth: xerostomia, mucositis, ulcers; whitish, lacy plaques on tongue and buccal surfaces, may be painful; tight oral aperture
- Esophageal strictures, stenosis, webs
- Blood: thrombocytopenia, anemia, eosinophilia, autoantibodies, hypo- or hypergammaglobulinemia
- Joints: stiffness, contractures, swelling
- Muscles: eosinophilic fasciitis, myositis
- Lung: bronchiolitis obliterans (obstructive), bronchiolitis obliterans organizing pneumonia (restrictive), pleural effusions
- Other: pericardial effusions, pericarditis, cardiomyopathy, nephrotic syndrome, peripheral neuropathy, genital ulceration
Diagnostic Tests & Interpretation
Diagnosis is often made on clinical grounds.
Lab
- Complete blood count with differential and Coombs test: autoimmune thrombocytopenia (most common), hemolytic anemia, and neutropenia; eosinophilia, resolves with treatment
- Blood smear: Howell-Jolly bodies due to functional asplenia of chronic GVHD
- Elevated ALT/AST without hyperbilirubinemia
- Vitamin D: often low; risk for osteoporosis
- Urinalysis: may show protein, glucose, blood
- Schirmer test: decreased tear production
- Pulmonary function tests
- Echocardiogram/electrocardiogram
- Fluorescein microscopy: punctate keratopathy
Imaging
- High-resolution chest CT: bronchiolitis obliterans
- Barium swallow: strictures, webs
Diagnostic Procedures/Other
- Endoscopy or colonoscopy with biopsy: apoptosis and loss of villi; GI tract GVHD
- Skin biopsy: localized epidermal atrophy
- Liver biopsy: bile duct damage reminiscent of primary biliary cirrhosis
- Rule out viral/fungal infections
- Analysis of pleural, pericardial fluid
Differential Diagnosis
- Acute GVHD
- Skin: drug reaction, chemoradiotherapy, viral exanthema, engraftment syndrome; TEN for grade IV skin GVHD
- Liver: hepatic veno-occlusive disease, total parenteral nutrition, drug toxicity, bacterial sepsis, or viral infection
- GI: diarrhea secondary to transplant conditioning regimen, infectious causes (e.g., Clostridium difficile, CMV, adenovirus), or opiate withdrawal
- Chronic GVHD
- Skin: keratosis pilaris, eczema, psoriasis
Alert
- In chronic GVHD, do not give live vaccines; may lead to symptomatic infection
- Sudden high fevers may indicate bacterial sepsis, may be overwhelming. Chronic GVHD patients often functionally asplenic; have profoundly impaired immune function
Treatment
Medication
- Acute GVHD (grades II-IV)
- 1st line: systemic steroids at 2 mg/kg/24 h for 7-14 days then quick taper; cyclosporine or tacrolimus if not taking as prophylaxis
- 2nd line: mycophenolate mofetil, sirolimus (rapamycin), antithymocyte globulin, and etanercept (experimental)
- Infliximab: steroid-refractory GI disease
- Visceral organ involvement requires urgent start of 2nd-line therapy.
- For isolated, mild skin GVHD, topical tacrolimus ointment and triamcinolone
- Chronic GVHD
- Steroids alone or with cyclosporine, sirolimus, tacrolimus, or mycophenolate mofetil
- Goal: steroids <0.5 mg/kg alternating days; with cyclosporine or tacrolimus
- Steroid-refractory GVHD
- Mycophenolate mofetil, sirolimus, pentostatin (investigational)
- Other options many off-label: antithymocyte globulin; rituximab; low-dose methotrexate in liver GVHD; thalidomide; hydroxychloroquine; imatinib; low-dose cyclophosphamide; etanercept; alefacept; alemtuzumab: high infection risk
- Oral rinses with dexamethasone: oral GVHD
- Ursodeoxycholic acid: hepatic GVHD
Additional Therapies
General Measures
- Prophylaxis for P. jiroveci pneumonia and pneumococcal infection
- Antifungal coverage if on multiple immunosuppressive agents
- Hypogammaglobulinemia: IVIG
- Monitor closely for viral reactivation.
- Skin care: Lubricate dry skin with petroleum jelly. Protect skin from injury. Avoid sunburn.
- Correct electrolyte imbalances for muscular aches and cramps.
- Nutrition consults for malnutrition and wasting.
- If chronic GVHD persists past 2-3 months or prednisone is needed at 1 mg/kg/day, alternative therapy should be used.
- Hospitalization may be required for hydration, nutritional support, IV medications, monitoring, treatment of infections, and other supportive care.
Additional Therapies
- Extracorporeal photophoresis: very effective for chronic skin GVHD; lower response rate if visceral organs involved
- Psoralen plus ultraviolet A is of some benefit in skin GVHD (lichenoid, not sclerotic).
- Mesenchymal stem cells (experimental)
- Artificial tears for sicca syndrome
- Physical therapy/range-of-motion exercises to prevent contractures
- Inhaled corticosteroids and azithromycin (experimental) for bronchiolitis obliterans
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- Steroids: osteoporosis, diabetes
- Calcineurin inhibitors: hypertension, renal dysfunction, hypomagnesemia
- Sirolimus: hyperlipidemia, leukopenia, microangiopathic hemolytic anemia
- Mycophenolate mofetil: GI discomfort, diarrhea, leukopenia
Prognosis
Prognosis of GVHD is based on severity.
- Acute GVHD: graded from I to IV based on organ involvement, percent of body surface area involved (skin), volume of diarrhea (gut), and/or elevation of serum bilirubin (liver). The higher the grade, the lower the long-term survival. Grade I survival is the same as for patients without GVHD; grade II, 60%; grade III, 25%; grade IV, 5-15%
- Acute GVHD: 50-60% of patients respond to corticosteroids plus cyclosporine or tacrolimus.
- Poor prognosis for survival: extensive skin involvement, progressive onset, GI involvement, thrombocytopenia, weight loss, and low Karnofsky performance status (40-60% survival)
- 50% of patients still require therapy 5 years after diagnosis of chronic GVHD.
Complications
- Mortality from GVHD after HSCT is usually related to infection.
- Rarely, patients die of hepatic failure or abdominal catastrophe.
- In transfusion-associated GVHD, death is usually from bone marrow aplasia with destruction of the host's marrow by donor lymphocytes.
Additional Reading
- Carpenter PA, MacMillan ML. Management of acute graft versus host disease in children. Pediatr Clin North Am. 2010;57(1):273-295. [View Abstract]
- Jacobsohn DA. Optimal management of chronic graft-versus-host disease in children. Br J Haematol. 2010;150(3):278-292. [View Abstract]
- Schlomchik WD. Graft-versus-host disease. Nat Rev Immunol. 2007;7(5):340-357. [View Abstract]
- Wolff D, Schleuning M, von Harsdorf S, et al. Consensus conference on clinical practice in chronic GVHD: second-line treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2011;17(1):1-17. [View Abstract]
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
- 996.85 Complications of transplanted bone marrow
- 996.85 Complications of transplanted bone marrow
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
- T86.09 Other complications of bone marrow transplant
SNOMED
- 234646005 Graft-versus-host disease (disorder)
- 402355000 Acute graft-versus-host disease
- 402356004 Chronic graft-versus-host disease
FAQ
- Q: Do all patients with acute GVHD get chronic GVHD?
- A: No. ~30% of patients <10 years of age who receive HLA-identical sibling HSCT will get acute GVHD, whereas only 13% will develop chronic GVHD. Chronic GVHD can develop in a patient who did not have acute GVHD; the prognosis is much more favorable than for the progressive form.
- Q: Do all severe chronic GVHD patients die?
- A: No. Occasionally, the GVHD will "burn out." This is rare, and the process by which it happens is not understood.