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Graft Versus Host Disease (GVHD)

Practice Essentials

Graft versus host disease (GVHD) is an immune-mediated condition resulting from a complex interaction between donor and recipient adaptive immunity.
Acute GVHD describes a distinctive syndrome of dermatitis (see the image below), hepatitis, and enteritis developing within 100 days after allogeneic hematopoietic cell transplantation (HCT). Chronic GVHD describes a more diverse syndrome developing after day 100. In addition to allogeneic HCT, procedures associated with high risk of GVHD include transplantation of solid organs containing lymphoid tissue and transfusion of unirradiated blood products.

Autologous graft versus host disease (GVHD) involv

Autologous graft versus host disease (GVHD) involving the skin of a patient’s arm appeared shortly after signs of engraftment appeared. The patient had undergone autologous peripheral blood stem-cell transplantation to treat ovarian cancer. Courtesy of Romeo A. Mandanas, MD, FACP.

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Signs and symptoms

Presentation in acute GVHD is as follows:

A pruritic or painful rash (median onset, day 19 posttransplantation; range, 5-47 days)

Pruritus from initially asymptomatic liver involvement, anorexia, weight loss, followed rarely by hepatic coma

Diarrhea, intestinal bleeding, cramping abdominal pain, and ileus

Diarrhea in acute GHVD is green, mucoid, watery, and mixed with exfoliated cells forming fecal casts. Voluminous secretory diarrhea may persist despite cessation of oral intake.

Upper GI enteric GVHD occurs in approximately 13% of patients who receive HLA-identical transplants and manifests as anorexia and dyspepsia without diarrhea. It is most common in older patients.

Chronic GVHD may be an extension of acute GVHD, may occur de novo in patients who never have clinical evidence of acute GVHD, or may emerge after a quiescent interval after acute GVHD resolves.
Manifestations are as follows:

Ocular – Burning, irritation, photophobia, and pain from lack of tear secretion

Oral and GI – Mouth dryness, sensitivity to acidic or spicy foods, dysphagia, odynophagia, and insidious weight loss

Pulmonary – Obstructive lung disease, with symptoms of wheezing, dyspnea, and chronic cough that is usually nonresponsive to bronchodilator therapy

Neuromuscular – Generalized or focal weakness, neuropathic pain, vision loss, muscle cramps, myalgia

Joints – Arthralgia, arthritis

Physical examination

Skin findings are as follows:

Maculopapular exanthema – Red-to-violet lesions that typically first appear on the palms of the hands, soles of the feet, cheeks, neck, ears, and upper trunk, sometimes progressing to involve the whole body; in severe cases, bullae may be observed, and vesicles may form

Lichenoid skin lesions or sclerodermatous thickening of the skin, which sometimes causes contractures and limits joint mobility

Jaundice from hyperbilirubinemia; patients who subsequently develop pruritus may exhibit excoriations from scratching

Ocular findings may include the following:

Acute GVHD – Hemorrhagic conjunctivitis, pseudomembrane formation, and lagophthalmos

Chronic GVHD – Keratoconjunctivitis sicca, which may lead to punctate keratopathy

Additional findings are as follows:

Oral – Atrophy of the oral mucosa, erythema, and lichenoid lesions of the buccal and labial mucosae in chronic GVHD

Pulmonary – Prolonged expiratory breathing phase (wheezes) from bronchiolitis obliterans

GI – Diffuse abdominal tenderness with hyperactive bowel sounds may accompany secretory diarrhea of acute GVHD; in severe ileus, the abdomen is silent and appears distended

Neuromuscular – Findings of myasthenia gravis, polymyositis, optic neuritis, arthritis may occur in chronic GVHD

Vaginitis and vaginal strictures have been described in chronic GVHD

See Presentation for more detail.

Diagnosis

Laboratory study results in GVHD are as follows:

CBC – Autoimmune cytopenias (eg, thrombocytopenia, anemia, leukopenia) may be observed with chronic GVHD

Liver function tests – Elevation of the alkaline phosphatase level, an early sign of liver involvement by GVHD; hypoalbuminemia is typically due to GVHD-associated intestinal protein leakage and a negative nitrogen balance

Serum electrolytes and chemistries (eg, potassium, magnesium, bicarbonate levels) may be altered; massive diarrhea and diminished oral intake can lead to serious electrolyte abnormalities

Other tests

Schirmer test – To measure the degree of tear formation by the lacrimal glands in chronic GVHD

Pulmonary function tests and arterial blood gas analysis – To identify obstructive pulmonary disease (eg, obliterative bronchiolitis) in chronic GVHD

Manometric studies of the esophagus

Imaging studies

Hepatic and Doppler sonography

Barium swallow study

Procedures

Skin punch biopsy

Upper GI endoscopy and biopsy in patients with persistent anorexia and vomiting

Flexible sigmoidoscopy or colonoscopy with biopsy of sigmoid or colonic lesions in patients with diarrhea

Liver biopsy (rarely done, usually only in patients with isolated hepatic findings)

See Workup for more detail.

Management

The criterion standard for primary prophylaxis of acute GVHD is cyclosporine for 6 months and short-course methotrexate in T-cell–replete allogeneic HCT (criterion standard); currently, tacrolimus is often substituted for cyclosporine because of its more potent immunosuppressant capacity and lower risk of nephrotoxicity. Antithymocyte globulin (ATG) is given before HCT in unrelated-donor transplants.

Primary therapy for acute GVHD is as follows:

For skin GVHD of stage I or II, observation or a trial of topical corticosteroids (eg, triamcinolone 0.1%) may be used

For grade II-IV acute GVHD, continuing the original immunosuppressive prophylaxis and adding methylprednisolone (commonly starting at 2 mg/kg/day in 2 divided doses); in patients who respond to initial therapy, the steroid will be tapered weekly thereafter until off 

Other therapies are ATG, cyclosporine, sirolimus 
 , mycophenolate mofetil (MMF), daclizumab, anti–interleukin-2 (IL-2) receptor, alone or in combination

Secondary therapy for acute GVHD is as follows:

ATG or multiple pulses of methylprednisolone (at doses higher than those used in initial therapy)

Tacrolimus, for GVHD with cyclosporine resistance or neurotoxicity or nephrotoxicity

MMF at 2 g daily, added to the steroid regimen

infliximab

or etanercept

Psoralen and ultraviolet A irradiation (PUVA), for cutaneous lesions

Ruxolitinib

Muromomab-CD3 (Orthoclone OKT3)

Humanized anti-Tac antibody to the IL-2 receptor

Primary therapy for chronic GVHD is as follows:

Prednisone, 1 mg/kg every day

Tacrolimus

Cyclosporine, 6 mg given every 12 hours every other day in patients at high risk for GVHD with thrombocytopenia

Sirolimus

Thalidomide

Secondary therapy for chronic GVHD is as follows:

Ibrutinib for adults who failed at least 1 treatment for chronic GVHD

MMF, added to standard tacrolimus, cyclosporine, sirolimus, and/or prednisone, for steroid-refractory chronic GVHD

Azathioprine, alternating cyclosporine/prednisone, or thalidomide for steroid-refractory chronic GVHD

Low-dose (100-cGy) total lymphoid irradiation to thoracoabdominal areas

Imatinib

Pentostatin

Belumosudil, for adults and children aged ≥12 years in whom 2 prior systemic therapies for chronic GVHD have failed

Ruxolitinib, for adults and children aged ≥12 years in whom 1 or 2 prior systemic therapies for chronic GVHD have failed

Treatment of cutaneous, musculoskeletal, or oral lesions of chronic GVHD includes the following:

Clofazimine, for treating cutaneous and oral lesions of chronic GVHD and as a steroid-sparing agent

PUVA therapy, for refractory cutaneous chronic GVHD

Extracorporeal photopheresis (a modification of PUVA treatment)

Rituximab, mainly for musculoskeletal and cutaneous chronic GVHD

See Treatment and Medication for more detail.

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