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Graft-Versus-Host Disease, Pediatric

Basics

Description

- 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

- 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

- 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

- 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 - 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

- 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

- 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

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 subtypesProgressive: extension of acute GVHDQuiescent: after resolution of acute GVHDDe novo: no prior acute GVHD

Epidemiology

  • Acute GVHD (grades II-IV): 10-80% of patients receiving T-cell-replete HSCT35-45% for human leukocyte antigen (HLA)-identical related donor bone marrow60-80% if 1-antigen HLA-mismatched unrelated donor bone marrow or peripheral stem cells35-65% if 2-antigen HLA-mismatched unrelated umbilical cord blood
  • Chronic GVHD: most common cause of late morbidity and mortality of allogeneic HSCT15-25% if HLA-identical related marrow40-60% if HLA-matched unrelated marrow54-70% if HLA-matched unrelated peripheral stem cells20% 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 doseHighest risk: with peripheral stem cellsLowest risk: with umbilical cord blood
  • Donor leukocyte infusions
  • Reactivation of viruses (e.g., HHV-6, CMV)
  • T-cell depletion decreases incidence.
  • Acute GVHD-specificHigher intensity conditioning regimenPrior pregnancies in female donorsGender mismatch
  • Chronic GVHD specificSeverity of acute GVHDMalignancy as indication for transplantationUse of total-body irradiationType 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 transplantationSelection of a histocompatible donorImmunosuppression (gold standard): cyclosporine or tacrolimus with a short course of methotrexateOther options: corticosteroids, sirolimus, mycophenolate mofetil, and low-dose cyclophosphamideDonor 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 responsesSeverity related to degree of HLA mismatch3 phases ending in "cytokine storm"Tissue damage by conditioning regimenPriming and activation of donor T cellsInfiltration 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 GVHDRash: usually 1st manifestation; pruritus or burning sensation can precede rash.Diarrhea, abdominal pain, and intestinal bleeding: unusual to precede skin diseaseAnorexia, nausea, vomiting, and dyspepsiaJaundice (liver involvement)
  • Chronic GVHDDry eyes and/or dry mouth, blurry vision, eye irritation, photophobia, eye painDifficulty swallowing or retrosternal painSensitivity to mint, spicy foods, or tomatoesWeight loss, failure to thrive, anorexia, nausea, vomiting, diarrheaDyspnea, wheezing, coughPoor wound healing, especially post traumaJoint stiffness, muscle cramps
  • Infections: pneumococcal sepsis, Pneumocystis jiroveci, fungal infections

Physical Exam

  • Acute/transfusion-associated GVHDSkin (most common site)Maculopapular rash of palms, soles; can become confluent erythrodermaSevere form: bullae formation, to even full-thickness necrosisGI tract: weight loss; profuse, watery, often green, and often bloody diarrheaLiver: jaundice; atypical findings: painful hepatomegaly, ascites, rapid weight gain
  • Chronic GVHDSkin (involved in almost every patient)Hyper- or hypopigmentation, xerosis (skin dryness), pruritus, scaling, patchy erythema, poikiloderma, skin atrophy; lichenoid, eczematous, and/or sclerodermatous changesAdvanced scleroderma: thickened, tight, and fragile skinHair: thin, fragile; premature grayingScalp: dry or seborrheicNails: dystrophic, fragile; entire nail lossMouth: xerostomia, mucositis, ulcers; whitish, lacy plaques on tongue and buccal surfaces, may be painful; tight oral apertureEsophageal strictures, stenosis, websBlood: thrombocytopenia, anemia, eosinophilia, autoantibodies, hypo- or hypergammaglobulinemiaJoints: stiffness, contractures, swellingMuscles: eosinophilic fasciitis, myositisLung: bronchiolitis obliterans (obstructive), bronchiolitis obliterans organizing pneumonia (restrictive), pleural effusionsOther: 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 GVHDSkin: drug reaction, chemoradiotherapy, viral exanthema, engraftment syndrome; TEN for grade IV skin GVHDLiver: hepatic veno-occlusive disease, total parenteral nutrition, drug toxicity, bacterial sepsis, or viral infectionGI: diarrhea secondary to transplant conditioning regimen, infectious causes (e.g., Clostridium difficile, CMV, adenovirus), or opiate withdrawal
  • Chronic GVHDSkin: 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 prophylaxis2nd line: mycophenolate mofetil, sirolimus (rapamycin), antithymocyte globulin, and etanercept (experimental)Infliximab: steroid-refractory GI diseaseVisceral organ involvement requires urgent start of 2nd-line therapy.For isolated, mild skin GVHD, topical tacrolimus ointment and triamcinolone
  • Chronic GVHDSteroids alone or with cyclosporine, sirolimus, tacrolimus, or mycophenolate mofetilGoal: steroids <0.5 mg/kg alternating days; with cyclosporine or tacrolimus
  • Steroid-refractory GVHDMycophenolate 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.