Pediatrics

Graft versus host disease

OVERVIEW: What every practitioner needs to knowAre you sure your patient has acute graft versus host disease? What are the typical findings for this disease?

Acute graft-versus-host disease (GVHD) is a condition caused by alloreactive donor T cells after a hematopoietic stem cell transplant (HSCT). Acute GVHD essentially represents donor T cells attacking host tissues. Typically, acute GVHD occurs after engraftment occurs. Engraftment usually occurs somewhere between 20 and 40 days after HSCT, depending on the stem cell source and the preparative regimen.

The most common manifestation of acute GVHD is a maculopapular rash. The rash is usually pruritic. It often begins on the palms, soles, and ears but can evolve after a few days to involve the whole body.

The other common manifestations of acute GVHD are abdominal pain and diarrhea. Usually, the diarrhea is secretory and associated with crampy abdominal pain. The diarrhea can sometimes be bloody.

The other common manifestation is liver involvement, which results from biliary duct damage. Elevation of total and direct bilirubin is seen, as is elevation in the alkaline phosphatase level. The patient can have icteric sclerae and jaundice. Finally, elevation of transaminase levels can be seen, which usually represents a more hepatitic injury pattern of acute GVHD.

Chronic graft versus host disease

Chronic GVHD usually has different manifestations and different timing. Manifestations of chronic GVHD can be protean but most typically will involve skin, mouth, and eyes.

Skin manifestations can range from mimimal hyper- or hypopigmentation to lichenoid rashes to sclerosis. Patients with sclerosis can have moveable or nonmoveable sclerosis.

Oral GVHD is manifested by erythema and lichen planus of the buccal mucosa. In more severe cases, mucoceles can be seen. The patient will complain of sensitivity to spicy or acidic foods. Severe pain can also occur.

Ocular GVHD is manifested by dry eyes resulting from damage to the lacrimal duct. A Schirmer test would show decreased tearing.

Other manifestations of chronic GVHD include pulmonary symptoms (dyspnea, shortness of breath, cough, and obstructive pattern on pulmonary function tests), fasciitis, decreased range of motion of joints, elevation of bilirubin levels, weight loss, abdominal pain, and diarrhea.

Chronic GVHD usually occurs later than 100 days after HSCT but can occur before that. Its diagnosis is based on manifestations and not timing. Manifestations of both acute and chronic GVHD are termed overlap syndrome, and patients with this syndrome have a poor prognosis.

Grading of acute graft versus host disease

Stages of GVHD are based on the degree that skin, gastrointestinal (GI) tract, and liver are affected. That staging is then used to determine the overall grade of the patient. Usually patients with grade III-IV GVHD have a much worse outcome than those with grade I-II GVHD ( Table 1).

Table 1.

Extent of Organ Involvement
Stage Skin Liver (Bilirubin) Gut (Stool Output/Day)
0 No GVHD rash <2 mg/dL <500 mL/d or persistent nausea(Child:<10 mL/kg/d)
1 Maculopapular rash <25% BSA 2-3 mg/dL 500-999 mL/d (Child: 10-19.9 mL/kg/d) or persistent nausea, vomiting, or anorexia, with a positive upper GI biopsy result
2 Maculopapular rash 25%-50% BSA 3.1-6 mg/dL 1000-1500 mL/d (Child: 20-30 mL/kg/d)
3 Maculopapular rash >50% BSA 6.1-15 mg/dL Adult: >1500 mL/d (Child: >30 mL/kg/d)
4 Generalized erythroderma plus bullous formation >15 mg/dL Severe abdominal pain with or without ileus
Grade
I Stage 1-2 None None
II Stage 3 or Stage 1 or Stage 1
III Stage 2-3 or Stage 2-4
IV Stage 4 or Stage 4

What other disease/condition shares some of these symptoms?

Acute GVHD is a clinical diagnosis but the practitioner may wish to do a biopsy to differentiate it from other manifestations that may be occuring at the same time.

Specifically, acute GVHD of the skin may be confused with viral exanthem or a rash resulting from medication. At times, a skin biopsy may help in differentiating the diagnosis. Similarly, gut GVHD could be confused with infection, so it is important to rule out viral and bacterial infections of the GI tract before assuming the diagnosis is GVHD. Sometimes cultures suffice; other times an endoscopy may be necessary.

What caused this disease to develop at this time?

The risk factors for acute GVHD are well defined. The most important factor is HLA disparity. Among siblings, patients receiving matched grafts have lower rates of GVHD than do those receiving HLA-mismatched grafts. In a large registry-based study of allogeneic matched-sibling bone marrow transplants (630 children with leukemia), the incidences of grade II-IV and grade III-IV acute GVHD were 28% and 11%, respectively.

For unrelated donor transplants, the greater the degree of HLA-mismatch, the higher the likelihood of developing acute GVHD and the worse the overall outcome. Recent data from the National Marrow Donor Program suggests that allele-level matching (high resolution) as opposed to group matching (low resolution) provides an advantage in reducing the likelihood of GVHD.

We have observed the same trends in pediatric GVHD. Up to the late 1990s, the approach was to match at HLA-A and -B at the group level and the HLA-DRB1 at the allele level. Using this approach with unmanipulated unrelated bone marrow led to an incidence of severe acute GVHD (grade III/IV) in the 30%-50% range in children.

There is increasing use of peripheral blood stem cell (PBSC) as a way of collecting cells from related or unrelated donors. No randomized study has been completed to determine if PBSC transplants change the incidence of GVHD or eventual outcome. However, there is a suggestion from a meta-analysis that acute GVHD is slightly increased (relative risk [RR], 1.16; P = .006) and chronic GVHD is increased (RR, 1.53; P <.001) when comparing PBSC to bone marrow transplants.

There are few reports of acute GVHD after PBSC transplants in pediatric patients. Eapen recently reported a similar incidence of grade II-IV and grade III-IV acute GVHD in PBSC transplants (N = 143) compared with bone marrow transplants (N = 630) in a large, retrospective registry study of pediatric leukemia patients. Incidence of grade II-IV acute GVHD was 27% and 28% and of grade III-IV acute GVHD was 13% and 11%, for PBSC and bone marrow transplant recipients, respectively.

Other factors can also increase the likelihood of acute GVHD. Older age of both recipient and donor increase the probability of GVHD. Sex mismatch, specifically a multiparous female donor into a male patient, increases the likelihood of GVHD. ABO mismatch can also increase the risk of GVHD.

A malignant as opposed to nonmalignant diagnosis leads to more GVHD. Furthermore, because of increased tissue damage, the intensity of the preparative regimen does appear to correlate with more acute GVHD. Higher doses of radiation give rise to more GVHD, and the more recent use of nonmyeloablative preparative regimens has led to lower incidence of acute GVHD in some studies.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Thrombocytopenia is one of the main findings that can be associated with GVHD, particularly chronic GVHD. However, this is not a sensitive or specific marker. It is associated with poor outcome of chronic GVHD. Laboratory findings associated with liver GVHD are high bilirubin and alkaline phosphatase levels, although patients may also present with transaminitis due to GVHD.

Would imaging studies be helpful? If so, which ones?

The main imaging study that can at times be helpful is a high-resolution chest CT scan in patients with chronic GVHD. In combination with pulmonary function tests showing an obstructive pattern, a high-resolution chest CT scan showing bronchiectasis can suggest lung GVHD.

If you are able to confirm that the patient has graft versus host disease, what treatment should be initiated?

The mainstay of treatment for acute GVHD is corticosteroid therapy. The practitioner should initiate methylprednisolone or prednisone at 2 mg/kg/d. This can be given orally or intravenously, depending on the symptoms of the patient. If the patient is being treated with a calcineurin inhibitor, that treatment should be optimized. If after 1 week the patient is worsening or not improving, additional therapies, such as photopheresis or administration of rapamycin, pentostatin, or mycophenolate can be considered. If there is improvement after 1 week, all efforts should be made to taper the steroids, given that corticosteroid therapy carries a high risk of infection.

What are the adverse effects associated with each treatment option?

The main concern with corticosteroids and any form of immunosuppression is that it enhances the risk for infection. This risk always needs to be considered against potential benefit in a patient with active GVHD. Other side effects of steroids are diabetes and hypertension. If used for many months, the patient may experience osteoporosis in the long term. It is always important to balance the prolonged need for steroids and their potential side effects against their benefits.

What are the possible outcomes of graft versus host disease?

Generally patients with grade I-II GVHD will recover well with therapy and will be able to discontinue corticosteroids after a few weeks. The likelihood of mortality is higher with grade III-IV GVHD and may approach 90% in some cases of very severe GVHD. Usually patients die of infection associated with their high degree of immunosuppression. About 50% of patients treated for acute GVHD who survive will experience chronic GVHD.

What causes this disease and how frequent is it?

The disease is caused by alloreactive donor T cells. The proposed pathophysiology of acute GVHD involves tissue damage during conditioning, release of inflammatory cytokines (such as tumor necrosis factor-alpha and interleukin-1) followed by donor cell activation. During donor cell activation there is an interplay between host dendritic cells and donor T cells, leading to Th1 polarization of donor T cells. These primed T cells are then able to cause damage of target tissues through apoptosis.

What complications might you expect from the disease or treatment of the disease?

The major complications that one expects are from treatment of the disease. Unfortunately, a significant proportion of patients with severe (grade III-IV) acute GVHD treated with high doses of immunosuppressive agents get infections (viral, fungal, or bacterial).

How can graft versus host disease be prevented?

The mainstay of prevention is selection of the most well-matched donor possible. Other methods of prevention of GVHD are depletion of T cells from the graft, although this may increase the risk of relapse (less graft versus leukemia) and infection (delayed immune reconstitution). Without GVHD prophylaxis, the incidence of GVHD would be virtually 100%. Therefore, patients usually receive a calcineurin inhibitor (FK506 or cyclosporine) plus methotrexate or mycophenolate mofetil after transplantation.

What is the evidence?

Hill, GR, Ferrara, JL. "The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation". Blood. vol. 95. 2000. pp. 2754-9.

(Highlights the importance of the gastrointestinal tract in the pathogenesis of GVHD)

Przepiorka, D, Weisdorf, D, Martin, P. "1994 Consensus Conference on Acute GVHD Grading". Bone Marrow Transplant. vol. 15. 1995. pp. 825-8.

(Key article on grading of acute GVHD)

Cahn, JY, Klein, JP, Lee, SJ. "Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: a joint Societe Francaise de Greffe de Moelle et Therapie Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study". Blood. vol. 106. 2005. pp. 1495-1500.

(Key article on grading of acute GVHD)

Eapen, M, Horowitz, MM, Klein, JP. "Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: the Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry". J Clin Oncol. vol. 22. 2004. pp. 4872-80.

(Highlights the importance of stem cell source on outcome)

Flomenberg, N, Baxter-Lowe, LA, Confer, D. "Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome". Blood. vol. 104. 2004. pp. 1923-1930.

(Highlights the importance of HLA matching on outcome)

Woolfrey, AE, Anasetti, C, Storer, B. "Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children". Blood. vol. 99. 2002. pp. 2002-8.

(Important publication on outcomes of unrelated marrow transplantation in children)

Rocha, V, Cornish, J, Sievers, EL. "Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia". Blood. vol. 97. 2001. pp. 2962-71.

(Unrelated cord blood is a common stem cell source used for transplants in children)

Locatelli, F, Zecca, M, Rondelli, R. "Graft versus host disease prophylaxis with low-dose cyclosporine-A reduces the risk of relapse in children with acute leukemia given HLA-identical sibling bone marrow transplantation: results of a randomized trial". Blood. vol. 95. 2000. pp. 1572-9.

(Randomized study of GVHD prophylaxis in children)

Lee, SJ, Zahrieh, D, Agura, E. "Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-versus-host disease: results of a randomized trial". Blood. vol. 104. 2004. pp. 1559-64.

(One of the few randomized studies for upfront therapy of acute GVHD)

Greinix, HT, Knobler, RM, Worel, N. "The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with severe acute graft-versus-host disease". Haematologica. vol. 91. 2006. pp. 405-8.

(Photopheresis is an important therapy for refractory GVHD)

Ongoing controversies regarding etiology, diagnosis, treatment

The major controversy is with regard to salvage therapy for GVHD. Although most agree that steroids represent the mainstay of therapy for initially diagnosed patients, there is controversy as to when to start salvage therapy and what to start. There are phase I and phase II data supporting a number of salvage therapies, including mycophenolate mofetil, rapamycin, photopheresis, and mesenchymal stem cells. However, there is a major lack of well-designed phase III studies in refractory GVHD, which is a very difficult population to study.

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