Acute Graft-Versus-Host Disease

Also known as: Engraftment syndrome

1. Description of the problem

What every clinician needs to know

Graft-versus-host disease (GVHD) is a disorder resulting from viable allogeneic T cells given to a recipient unable to reject these T cells. The most common setting for the development of GVHD is allogeneic hematopoietic stem cell transplantation. Blood transfusion-associated acute GVHD may also occur.

Continue Reading

Acute GVHD is commonly defined as GVHD occurring within 100 days of allogeneic transplantation, although recent classifications include late-onset acute GVHD (after day 100) and an overlap syndrome (acute and chronic GVHD).

Hyperacute GVHD is usually defined as GVHD occurring within 14 days of transplantation.

Engraftment syndrome is a conglomerate of signs and symptoms related to pro-inflammatory cytokine release that occurs immediately before or at the time of neutrophil engraftment. Engraftment syndrome is described in both autologous and allogeneic transplant recipients but is more severe in the latter.

Clinical features

Clinical presentation of acute GVHD

  • Skin rash is the most common manifestation (~80%). The classical rash is maculopapular; it may be pruritic or not. It is often described as starting on the ears, palms, and soles, but this is not by any means absolute. It can be difficult to differentiate clinically from a drug rash. In its worse form acute skin GVHD can lead to blistering, desquamation and ulcerations. A rash upon engraftment should be considered to be GVHD unless proven otherwise.

  • Gastrointestinal involvement occurs in about 55% of cases. Upper GI GVHD presents as anorexia, nausea and vomiting and weight loss. Lower GI GVHD presents as a secretory diarrhea. In its worse forms patients may develop an ileus, or bleeding from mucosal ulcerations. Again, profuse watery diarrhea upon engraftment should be considered GVHD unless proven otherwise.

  • Liver involvement will occur in up to 50% of cases and originally presents as transaminitis and hyperbilirubinemia. It is often seen in conjunction with skin and/or gut GVHD. Liver GVHD can be difficult to differentiate from veno-occlusive disease of the liver (VOD); however, VOD is usually associated with right upper quadrant pain and impressive weight gain. VOD can also occur as early as day +1, which is too early for GVHD.

  • Other organ involvement includes lungs and eyes. Acute ocular GVHD is mostly seen in patients with severe acute GVHD involving other organs. Acute lung GVHD involves mostly patients with engraftment syndrome or hyperacute GVHD.

Clinical manifestations of engraftment syndrome

  • The clinical signs of engraftment syndrome occur in the peri-engraftment period.

  • High fever, non-cardiogenic pulmonary edema sometimes leading to respiratory failure and/or pulmonary hemorrhage should be recognized immediately as engraftment syndrome. Engraftment syndrome is often a precursor to acute GVHD.

Key management points

Optimal acute GVHD management requires the following:

  • Early intervention with initiation of treatment with corticosteroids

  • Early recognition of treatment failure and initiation of second-line therapy

  • Early recognition and treatment of engraftment syndrome to prevent severe respiratory deterioration

  • Proper monitoring of immunosuppressive medications to prevent renal failure and other complications

  • Constant alertness for and screening of infectious complications to prevent the most common cause of mortality in GVHD patients

2. Emergency Management

Engraftment syndrome, if presenting with non-cardiogenic pulmonary edema or pulmonary hemorrhage, requires urgent management.

  • Initiation of corticosteroids, usually Solu-Medrol 1000 mg IV stat

  • Careful fluid management to prevent fluid overload

  • Transfusion of platelets in thrombocytopenic patients

3. Diagnosis

Establishing the diagnosis of GVHD

  • Early diagnosis of acute GVHD is important for timely initiation of therapy and prevention of morbidity and mortality. Whenever possible, pathologic confirmation should be obtained; however, this should not delay treatment. Treatment can and should be initiated based on the clinical evaluation. If pathological findings are diagnostic of another entity, treatment can then be slowly withdrawn.

  • Cutaneous acute GVHD is characterized by necrosis of the basal layer epithelial cells seen on punch biopsy. Dyskeratotic or apoptotic keratinocytes is most commonly seen. Continued damage leads to necrosis of the epidermis.

  • Biopsies of the stomach and sigmoid are often obtained. A colonoscopy is rarely necessary and a sigmoidoscopy is usually preferred to minimize risks. Pathologically, exploding or missing crypt cells are commonly seen. It may be important in some cases to rule out the presence of certain viruses such as cytomegalovirus (CMV). Multiple pathologies can be seen concomitantly, such as pseudomembranous colitis, CMV and GVHD. Again, a negative biopsy does not exclude the diagnosis in the setting of clinical findings.

  • The liver is the least often biopsied of the major organs due to the risk and overall poor specificity. Typically there is portal lymphocytic infiltrates and bile duct damage. Hyperbilirubinemia is a patient with skin and/or gut GVHD should be considered to be liver GVHD.

Clinical management of acute GVHD

  • Acute GVHD staging and grading

    Acute GVHD staging and grading is important to establish treatment and monitor response.

Table I. Consensus criteria for organ staging of acute GVHD

Table I.
Staging Skin Liver Gut
Organ Staging0 No rash due to GVHD Bilirubin <2 mg/dL None
I Maculopapular rash <25% of body surface area without associated symptoms Bilirubin from 2 mg/dL to <3 mg/dL Diarrhea >500-1500 mL/day; nausea and emesis
II Maculopapular rash or erythema with pruritus or other associated symptoms covering ≥ 25% and <50% of body surface area or localized desquamation Bilirubin from 6 mg/dL to < 15 mg dL Diarrhea > 1500 mL/day; nausea and emesis
III Generalized erythroderma or symptomatic macular, papular or vesicular eruption with bullous formation or desquamation covering ≥ 50% of the body surface area Bilirubin from 6 mg/dL to < 15 mg/dL Diarrhea > 1500 mL/day; nausea and emesis
IV Generalized exfoliative dermatitis or ulcerative dermatitis or bullous formation Bilirubin > 15 mg/dL Severe abdominal pain with or without ileus
Adapted from Przpiorka et al, 1995.7

Table II. Overall clinical grading of acute GVHD

Table II.
Grade Skin Liver Gut Functional
0 (none) 0 0 0 0
1 (mild) 1 to 2 0 0 0
2 (moderate) 1 to 3 1 1 1
3 (severe) 2 to 3 2 to 3 2 to 3 2
4 (life-threatening) 2 to 3 2 to 3 2 to 3 2 to 4

Adapted from Przpiorka et al., 1995.7

*Zubrod performance status

4. Specific Treatment

Primary treatment of acute GVHD

The accepted gold standard for the treatment of acute GVHD is corticosteroids, usually in the form of prednisone or methylprednisolone at a dose of 2 mg/kg/d. Patients should remain on a calcineurin inhibitor and conversion to IV administration may be necessary to maintain adequate levels if oral absorption is impaired by gut involvement.

Engraftment syndrome with non-cardiogenic pulmonary edema or pulmonary hemorrhage leading to respiratory compromise is treated with much higher doses of corticosteroids, Solu-Medrol 10 mg/kg/d or 1000 mg IV daily x 3 followed by a 50% taper every 3 days until reaching 2 mg/kg/d. Subsequently, an acute GVHD steroid taper should be initiated as described below.

Grade 1 GVHD (skin stage 1 or 2) may be treated with topical steroids only, such as triamcinolone cream 0.1% or 0.5% BID, avoiding face and groin. Other topicals such as topical tacrolimus or hydrocortisone may be more appropriate for the face.

Grade 2 GVHD may be treated orally, especially if there is no gut involvement, with prednisone 1 mg/kg PO BID; otherwise patients should receive IV Solu-Medrol 0.5 mg/kg Q6H.

Grade 3 to 4 GVHD is treated with Solu-Medrol 2 mg/kg x 1, followed by 0.5 mg/kg Q6H.

Upper GI GVHD as sole involvement may be treated with Solu-Medrol 1 mg/kg/d or its prednisone equivalent.

Patients should be reassessed at 3-5 days and if responding, a taper can be initiated after 7-14 days of treatment, with a reduction in steroids of 10-20% every 5 days.

70% of patients will show a response within 5 days. Patients with progression within 3 days (upgrading) or no response within 5 days (no downgrading) should be given second-line therapy.

Medications used in the management of acute GVHD

Tacrolimus and cyclosporine inhibit the cytoplasmic enzyme calcineurin critical for the activation of T cells. These drugs require close monitoring of serum levels. Levels should be drawn at least twice weekly and not from a central venous catheter that was at any time used for administration of the drug. Therapeutic tacrolimus levels are usually between 6 and 12, for cyclosporine between 200-400. Inadequate monitoring of these drugs can lead to serious complications, including renal failure.

These drugs have also been associated with transplant-associated microangiopathy (TAM) and neurotoxicity, which may require discontinuation. TAM usually presents as severe hypertension, intravascular hemolysis, thrombocytopenia and eventually seizures. After resolution, it may be possible to re-initiate treatment with these drugs, targeting a much reduced serum level.

Corticosteroids are associated with multiple toxicities, especially with long-term usage, including diabetes, myopathy, osteoporosis, cataracts and avascular necrosis.

Sirolimus is an mTOR inhibitor. It is structurally similar to tacrolimus but does not inhibit calcineurin. Sirolimus levels should also be monitored at least weekly and the dose adjusted accordingly. Used in conjunction with tacrolimus it may be associated with an increased risk of TAM.

ATG consists of horse- or rabbit-derived antibodies against human T cells. ATG causes severe immunosuppression and increases the risk of infections. Post-transplant lymphoproliferative disorder (PTLD), which is an EBV-driven lymphoma, is a possible complication of ATG.

Second-line treatment of acute GVHD

There is no established standard of care for second-line treatment. Early initiation of second-line therapy for patients meeting criteria (upgrading at 3 days or no downgrading at 5 days) has been associated with improved survival. ATG may be the most commonly used agent. Rabbit ATG is administered at a dose of 1.25 mg/kg IV every other day x 3 doses. Corticosteroids and calcineurin inhibitors should be continued. The overall response rate is about 55%, with skin having the best chance of response.

Other agents include sirolimus, mycophenolate mofetil, pentostatin, rituximab and others. None of these has been proven to improve survival, as increasing immunosuppression leads to infectious complications.

Patients requiring second-line therapy for steroid-refractory acute GVHD have an overall 1-year survival of approximately 30%. Participation in clinical trials is encouraged.

5. Disease monitoring, follow-up and disposition

Supportive care

Infectious disease prophylaxis and monitoring is important as most GVHD-related deaths are infectious in origin.

Patients should remain on their prophylactic antibiotics, including antivirals, antifungals, and Pneumocystis carinii prophylaxis.

The clinician should be alerted that bacterial infections, including bacteremia, may not be accompanied by fevers or classical manifestations in the severely immunocompromised host. Sudden clinical deterioration should prompt a search for an infectious assault.

Screening for CMV by PCR should be done at least weekly. CMV prophylaxis may be considered in high-risk patients (CMV IgG-positive recipients). Patients who receive antithymocyte globulin (ATG) or have certain clinical signs (such as falling blood counts) should be monitored for Epstein-Barr virus (EBV) PCR at least weekly.

BK virus-associated hemorrhagic cystitis is common and initiation of treatment with intravenous or intravesicular cidofovir may be needed.

Gut GVHD may require parenteral nutrition, and octreotide may be helpful in cases of severe diarrhea.


Toxicity from the preparative regimen (chemotherapy and/or radiation) induces the release of pro-inflammatory cytokines, which in turn promotes and expands the recipient’s antigen-presenting cells and the donor T cells. This is why regimen-related toxicity is associated with a higher risk of acute GVHD.

Alloreactive T cells expand and differentiate.

Activated T cells migrate to target organs such as skin, gut, liver, lung, eyes.

Effector T cells cause damage of the target organs or tissues, causing more inflammation and perpetuating the cycle.


Risk factors

The incidence of acute GVHD increases with the HLA disparity between the donor and recipient. Outside of HLA identify, minor histocompatibility antigens contribute to the disease development. HLA-identical sibling transplants have a risk of GVHD of approximately 40%. This increases to ~60% for matched unrelated donor recipients and increases further for recipients of unrelated donors with HLA mismatches. Umbilical cord blood transplants have a reduced incidence of acute GVHD and a certain level of HLA disparity is acceptable. Nonetheless, cord blood recipients are also at risk of GVHD.

Regimen-related toxicity can significantly increase the risk of GVHD by initiating the cascade, which starts with the release of pro-inflammatory cytokines.

Other secondary risk factors include female-to-male transplants, donor pregnancies, ABO disparity, infections such as Clostridium difficile, and other events that prime the immune system.

Prevention of GVHD

Calcineurin inhibitors (cyclosporine or tacrolimus) constitute the backbone of GVHD prophylaxis. Adequate serum levels of these drugs need to be maintained for effectiveness and to prevent toxicity. Cyclosporine or tacrolimus is initiated a day or two prior to the transplant, and in patients without evidence of GVHD it is slowly tapered starting on day 100.

Calcineurin inhibitors are usually used in combination with other immunosuppressive agents such as low-dose methotrexate, sirolimus or mycophenolate mofetil.

Prevention of transfusion-associated GVHD is done by irradiating blood products. This is especially important for patients with immunocompromised immune systems such as patients receiving chemotherapy and patients with thymic hypoplasia, Wiskott-Aldrich syndrome and others. Immunocompetent hosts are at risk if receiving blood products from donors homozygous for an HLA haplotype. This mostly applies to patients receiving blood products from relatives.

What's the evidence?

Przepiorka, D. “1994 Consensus conference on acute GVHD grading”. Bone Marrow Transpl. vol. 15. 1995. pp. 825-8.

Socie, G. “Acute graft-versus-host-disease from the bench to the bedside”. Blood. vol. 114. 2009. pp. 4327-36.

Ferrara, J. “Graft-versus-host-disease”. Lancet. vol. 373. 2009. pp. 1550-61.

Spitzer, TR. “Engraftment syndrome following hematopoietic stem cell transplantation”. Bone Marrow Transpl.. vol. 27. 2001. pp. 893-8.

MacMillan, ML. “Response to 443 patients to steroids as primary therapy for acute graft-versus-host-disease: comparison of grading systems”. Biol Blood Marrow Transpl. vol. 8. 2002. pp. 387-94.

MacMillan, ML. “Early antithymocyte globulin therapy improves survival in patients with steroid-refractory acute graft-versus-host-disease”. Biol Blood Marrow Transpl. vol. 8. 2002. pp. 40-6.