Acute graft-versus-host disease

Acute graft-versus-host disease

What every physician needs to know about acute graft-versus-host disease:

Acute graft-versus-host-disease (acute GVHD) occurs when lymphocytes from another person are able to survive and proliferate in a patient; it is one of the most serious complications of allogeneic bone marrow transplantation (BMT).

Rare causes of acute GVHD include maternal transfer of lymphocytes via the placenta to an immunodeficient infant, and transfusion of non-irradiated blood to a patient whose immune system cannot reject the donor lymphocytes, either due to immunodeficiency, histocompatibility, or transient immunocompromise from large volume transfusion or bypass. Outside of these rare settings, acute GVHD is typically only seen in the context of allogeneic BMT (bone marrow transplantation).

The risk of acute GVHD is related to many clinical factors including:

  • HLA (human leukocyte antigen) matching

The better matched the donor is to the recipient, the less the risk.

  • Donor type

Unrelated adult donors confer the greatest risk of acute GVHD; sibling donors have less risk.

  • Stem-cell source

Several studies have shown that peripheral blood stem cells carry greater risk for acute GVHD than bone marrow, but this finding is still controversial.

  • Age

Children are at lower risk of developing acute GVHD than adults.

  • Donor age

Older donor age has been associated with increased risk of acute GVHD.

  • Donor gender

Female donors increase the risk of acute GVHD in male recipients.

  • Transplant conditioning intensity

Reduced or non-myeloablative transplants reduce the incidence, and delay the onset of acute GVHD.

  • Unrelated cord-blood transplants result in less acute GVHD for the same degree of HLA-mismatch

At this time, most cord-blood units are only partially matched to the recipient.

  • acute GVHD prophylaxis regimen

Ex vivo T-cell depletion or in vivo administration of anti-T-cell antibody therapies around the time of donor graft infusion (such as antithymocyte globulin or alemtuzumab) decreases the risk of acute GVHD.

Acute GVHD is staged on a scale of 0 to IV based on a composite score derived from each of the three target organs (skin, liver, GI [gastrointestinal] tract). (Figure 1)

Figure 1.

GVHD staging. Adapted from Glucksberg et al, Transplantation 1974; 18:295-304.

What features of the presentation will guide me toward possible causes and next treatment steps:

Although acute GVHD can develop at any time following allogeneic BMT, the clinical symptoms typically develop between 3 to 4 weeks after the transplant in one of the classic target organs – the skin, liver or GI tract.

Clinical features include:

  • Skin

Maculopapular rash, commonly pruritic, often involving the palms and soles at first, but can spread to the entire body surface and, in severe cases, blister or ulcerate. Early stages can be difficult to distinguish from drug rash.

  • Liver

Features of cholestasis predominate with either elevated bilirubin levels in the blood or clinical jaundice. Elevated transaminase levels can occur around the initiation of liver GVHD, but are not a predominant feature.

  • GI tract

Usually presents as diarrhea from either the small intestine or colonic involvement. Nausea, vomiting, and anorexia are common manifestations of upper GI GVHD. Abdominal cramping, ileus, and bloody diarrhea are often seen in cases of more severe GI GVHD.

GVHD staging guides treatment steps. The overall GVHD grade is a composite score of the target organ stages (skin, liver, GI tract). (Figure 1)

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Acute GVHD is a clinical diagnosis. Laboratory studies are not required (other than an elevated bilirubin which is necessary to diagnose liver GVHD). Acute GVHD biomarkers in the plasma may become useful for diagnostic and prognostic purposes in the next few years, but at present they are only used in research settings. However, biopsies of affected organs (skin, upper GI tract, lower GI tract, liver) can be useful in confirming the clinical impression.

Pathological findings, such as vacuolar interface dermatitis with apoptotic keratinocytes for skin GVHD and epithelial cell apoptosis in the intestinal mucosa for GI GVHD, are often seen.

Infectious etiologies for diarrhea should be ruled out, such as Clostridium difficile, rotavirus, and adenovirus infections.

A drug rash can usually be distinguished from skin GVHD on biopsy.

Endoscopic evaluation can help identify other causes of GI symptoms such as nausea, vomiting, and diarrhea such as gastritis or Cytomegalovirus (CMV) colitis.

What conditions can underlie acute graft-versus-host disease:

Acute GVHD is a clinical diagnosis that is typically only suspected in the appropriate clinical scenario, primarily allogeneic BMT, but rare cases of transfusion-associated or maternal transfer of lymphocytes into an immunocompromised neonate can result in acute GVHD.

When do you need to get more aggressive tests:

Because acute GVHD is the primary cause of non-relapse mortality in allogeneic BMT, it is important to aggressively test for acute GVHD relatively early after the diagnosis is suspected. Tissue biopsies obtained very early in the disease course are sometimes non-diagnostic, but that should not preclude re-biopsy and/or treatment if the diagnosis is strongly suspected.

What imaging studies (if any) will be helpful?

Imaging studies are generally not helpful in the diagnosis of acute GVHD. Confirmation of ileus by abdominal CT (computed tomography) scan can be helpful during management.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?


Prevention is the most important strategy to limit acute GVHD. The primary aim of prevention is to deplete T-cells or prevent their proliferation in response to host antigens. There are numerous methods to achieve this goal, and institutional preference plays a large part in the selection of a GVHD prevention therapy.

Briefly, T-cell depletion, either in vitro or in vivo, can be effective in preventing severe GVHD, but are associated with increased risk of relapse, infection, and delayed immune reconstitution. The combination of a calcineurin inhibitor (tacrolimus or cyclosporine) with either mycophenolate or methotrexate is the most common GVHD prevention therapy. The risk of GVHD grade II or higher with this approach is 30 to 80% (based on the risk factors listed above) with the degree of the HLA match and donor type being the most important. HLA matched sibling donor transplant recipients have a 25 to 45% incidence of acute GVHD, compared to a 60 to 80% incidence in HLA mismatched unrelated donor transplant recipients.

As an alternative, highly mismatched haploidentical transplants (e.g., parent into child) can be performed with acceptable rates of acute GVHD by administering high dose cyclophosphamide early post-transplant (days 3 and 4). This strategy depletes activated, proliferating T cells while largely sparing quiescient donor T cells. This approach can be particularly useful for patients who lack an HLA-match within their family or the unrelated donor registries.

Corticosteroid therapy

Acute GVHD grade I (limited skin rash less than 50% BSA [body surface area]) can often be treated with topical corticosteroid therapy alone. Approximately 50% of patients who present with GVHD grade I will progress to higher grade GVHD and require more intensive treatment. There is no reliable way to predict who will develop progressive GVHD, therefore, some clinicians choose to initiate systemic corticosteroid therapy in patients at high risk for developing a more severe GVHD, such as recipients of unrelated donor transplants or when GVHD has developed within 2 weeks of transplant. There is no convincing data to advise for or against this approach.

The standard therapy for acute GVHD grade II or higher is prompt initiation of high-dose corticosteroid therapy (prednisone 2mg/kg/d or equivalent methylprednisolone dose). Topical steroids for skin GVHD and non-absorbable steroids, such as oral beclomethasone for GI tract GVHD are useful adjunctive therapy.

Complete gut rest for lower GI tract GVHD is usually initiated promptly to minimize the risk of developing ileus or painful abdominal cramping. Reintroduction of a diet as the disease responds to therapy is a stepwise, slow process, starting with small volumes of clear liquids and advancing with the easiest to digest foods first.

What other therapies are helpful for reducing complications?

Corticosteroid related complications are among the most serious consequences of acute GVHD.

Prompt initiation of broad anti-infective coverage for bacterial, pneumocystis, viral, and fungal infections, especially with Aspergillus coverage, can be life-saving. Monitoring for and preemptive treatment of Cytomegalovirus (CMV) activation in at risk patients is also essential. All patients are at risk for CMV reactivation unless both donor and recipient where known to have negative CMV serology prior to transplant.

Other complications such as hypertension, diabetes, osteoporosis, and myopathy require constant monitoring and management. Renal impairment in patients treated with calcineurin inhibitors can be avoided or minimized by ensuring adequate hydration.

What should you tell the patient and the family about prognosis?

Approximately 50 to 65% of patients with acute GVHD respond to corticosteroid therapy within 4 weeks. Failure to respond to treatment within 4 weeks (that is, an improvement in GVHD grade by at least one grade) is associated with a poor prognosis; the 6 month mortality rate in these patients is 45 to 65%.

Patients who develop grade IV GVHD have a particularly poor prognosis with mortality rates approaching 90%.

Patients with steroid responsive GVHD have a better prognosis, but the 2 year non-relapse mortality is still 20 to 35%, with deaths most commonly due to infections or chronic GVHD. The development of acute GVHD is a major risk factor for chronic GVHD, which can become a debilitating illness in around one-third of cases.

“What if” scenarios.

Inadequate response to initial treatment

An inadequate response to initial treatment with corticosteroids should lead to the initiation of second line therapy. Standard indications for starting second line therapy include worsening of the GVHD grade after 3 to 5 days of systemic treatment or lack of response within 7 to 14 days.

Unfortunately, there is no standard approach for this scenario and large numbers of patients fail to respond. Second line agents that have shown some efficacy include antibody therapy (antithymocyte globulin, alemtuzumab), mycophenolate, TNF (tumor necrosis inhibitors (etanercept, infliximab), extracorporeal photopheresis, and pentostatin.

Flares during steroid tapers

Flares of GVHD during steroid tapers are another common scenario. These patients are considered to have steroid-dependent GVHD. Reversal of the steroid taper is almost universally performed, but the addition of steroid-sparing immunosuppressants, should be considered.

Management of life-threatening infections

One of the most challenging scenarios is management of life-threatening infections such as invasive fungal infections or end-organ viral diseases, such as CMV pneumonitis in patients with steroid-dependent GVHD. In this situation, the addition of steroid-sparing therapies, such as extracorporeal photopheresis may facilitate a successful steroid taper.

Skin breakdown

Excellent skin care is an important component of management. Blistering in severe skin GVHD can be managed like burns or other similar wounds. All patients, even those without skin GVHD, should be advised to avoid/minimize ultraviolet light exposure with clothing and sunscreen.

Severe diarrhea

The judicious use of antimotility agents can be helpful in controlling GVHD-related diarrhea. Octreotide infusions can occasionally be helpful as an adjunctive therapy for poorly responding, profuse diarrhea. Patients with GI tract diarrhea may be kept on gut rest for prolonged periods; therefore, early initiation of parenteral nutrition is important.

Debilitation and myopathy

Debilitation and myopathy from prolonged high-dose steroid therapy should be avoided/minimized with physical therapy.

Risk of osteoporosis

Osteoporosis prophylaxis is important in order to avoid later onset of fractures, such as vertebral compression fractures which can be very painful. Avascular necrosis is another common complication.


Acute GVHD is the consequence of donor T-cells responding to host antigens. Damage to the recipient tissues by the transplant conditioning regimen increases the likelihood of GVHD. The release of pro-inflammatory cytokines increases the expression of receptors on antigen-presenting cells (APCs), enhancing cross presentation of minor histocompatibility antigens to donor T-cells. Donor T-cells proliferate and secrete additional inflammatory cytokines, such as TNF. Target organ damage is the consequence of both cellular effectors and soluble factors like TNF.

What other clinical manifestations may help me to diagnose acute graft-versus-host disease?

At each encounter, a careful history for target organ symptoms should be obtained.

Pruritus sometimes precedes development of skin GVHD rash. Nausea, anorexia, and weight loss can signal the presence of upper GI-tract GVHD, but are often overlooked initially. Abdominal cramping, loose stools, watery or bloody diarrhea should prompt further work-up.

A thorough skin exam is an important aspect of every encounter in the at risk patient. A maculopapular rash is stereotypical, but sometimes erythema is the presenting finding. Rash involving the palms or soles in the at-risk patient is usually GVHD.

What other additional laboratory studies may be ordered?

Total bilirubin levels are mandatory as part of the acute GVHD staging. Eosinophilia on a complete blood count differential, while non-diagnostic, can be a clue to GVHD presence or impending onset.

What’s the evidence?

Flowers, ME, Inamoto, Y, Carpenter, PA. "Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria". Blood. vol. 117. 2011. pp. 3214-9.

(Multiple studies in the 1990's evaluated risk factors for acute GVHD. This recently published large study from a single center confirmed and extended prior observations. Of note, recipient age was not a statistically significant risk in this study.)

Jagasia, M, Arora, M, Flowers, ME. "Risk factors for acute GVHD and survival after hematopoietic cell transplantation". Blood. vol. 119. 2012. pp. 296-307.

(Analysis of over 5000 related and unrelated donor transplant's defined risk factors for acute GVHD.)

Rühl, H, Bein, G, Sachs, UJ. "Transfusion-associated graft-versus-host disease". Transfus Med Rev. vol. 23. 2009. pp. 62-71.

(Excellent review of settings in which GVHD can develop, other than allogeneic bone marrow transplantation.)

Ferrara, JL, Levine, JE, Reddy, P, Holler, E. "Graft-versus-host disease". Lancet. vol. 373. 2009. pp. 1550-61.

(Comprehensive state of the art review of GVHD pathophysiology, prevention, treatment, and supportive care recommendations.)

Levine, JE, Logan, BR, Wu, J. "Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a Blood and Marrow Transplant Clinical Trials Network study". Blood. vol. 119. 2012. pp. 3854-60.

(This paper demonstrated that plasma GVHD biomarker concentrations measured at onset and during treatment in a multi-center study can predict treatment response and survival.)

Bashey, A, Zhang, X, Sizemore, CA. "T-cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplantation". J Clin Oncol. vol. 31. 2013. pp. 1310-6.

(Recent comparative analysis demonstrated similar rates of acute GVHD after haploidentical transplants given post-transplant, high dose cyclophosphamide when compared to conventional related and unrelated donor transplants.)

MacMillan, ML, Weisdorf, DJ, Wagner, JE. "Response of 443 patients to steroids as primary therapy for acute graft-versus-host disease: comparison of grading systems". Biol Blood Marrow Transplant. vol. 8. 2002. pp. 387-94.

(Highly cited paper describing expected treatment outcomes for patients treated for acute GVHD at a single center.)

Levine, JE, Logan, B, Wu, J. " Graft-versus-host disease treatment: predictors of survival". Biol Blood Marrow Transplant. vol. 16. 2010. pp. 1693-9.

(Recent analysis of factors predictive for response and survival from a multicenter study of novel GVHD treatments.)

Pidala, J, Anasetti, C. "Glucocorticoid-refractory acute graft-versus-host disease". Biol Blood Marrow Transplant. vol. 16. 2010. pp. 1504-18.

(Comprehensive review of treatment options for steroid refractory GVHD.)

Couriel, D, Carpenter, PA, Cutler, C. "Ancillary therapy and supportive care of chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report". Biol Blood Marrow Transplant. vol. 12. 2006. pp. 375-96.

(A workshop organized by the NIH (National Institutes of Health) developed recommendations for ancillary therapy and supportive care for chronic GVHD. These recommendations are highly applicable for patients requiring prolonged therapy for acute GVHD.)

Glucksberg, H, Storb, R, Fefer, A. "Clinical manifestations of graft-versus host disease in human recipients of marrow from HL-A-matched sibling donors". Transplantation. vol. 18. 1974. pp. 295-304.

(The data used in the figure within this chapter is based on the data in this article.)
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