Acute graft-versus-host disease (aGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT) in children. Although 30% to 50% of children respond to corticosteroids as initial therapy, the optimal initial or second-line therapies have not yet been determined. Newer approaches with combination therapy, novel agents, monoclonal antibodies, and/or cellular therapies show some promise but require prospective well-designed trials that include children to establish their efficacy. This article reviews the clinical presentation, treatment, and practical management guidelines for children with aGVHD.
The most significant immunologic barrier to successful hematopoietic stem cell transplantation (HSCT) is acute graft-versus-host disease (aGVHD), which can result in life-threatening inflammation and tissue destruction. The current model of aGVHD continues to invoke 3 collaborative phases: (1) tissue damage induced by the preparative regimen; (2) priming and activation of donor T cells, with CD8 T cells being stimulated by residual host antigen-presenting cells (APCs) and CD4 T cells being stimulated by donor APCs presenting host-derived antigens; and (3) target tissue damage induced directly by cytotoxic T cells and indirectly by inflammatory cytokines. In addition to αβ T cells, other cell populations that include natural killer (NK) cells, NK T cells and γδ T cells, conventional and plasmacytoid dendritic cells, and regulatory T cells (Tregs) seem to have important modulatory functions in aGVHD and further understanding may offer future novel approaches to management. Meanwhile, donor T cells that recognize disparate recipient alloantigens are central mediators of GVHD and remain the focus of current therapies.
The focus of this article is to guide the clinician in the various clinical presentations of aGVHD and initial (primary) therapy. In addition, secondary therapeutic options are reviewed for children who have failed primary therapy and suggestions are offered recognizing that there is no standard approach. Most of what is known about aGVHD therapy has arisen from trials that enrolled on adults with or without children. Whenever specifics pertain to children, they are highlighted in this paper. The prevention of aGVHD includes the avoidance of known risk factors (predominantly HLA-disparity), immunosuppressive pharmacotherapies, and cellular approaches that are reviewed in the literature.
Diagnosis and classification of acute GVHD
Historically, GVHD was categorized as acute or chronic based on time of presentation; GVHD before day 100 was known as acute, and after day 100 it was known as chronic. This classification was based on patients transplanted with HLA-identical sibling bone marrow (BM) after receiving myeloablative conditioning. In the last 20 years, HSCT has become more complex, particularly with the use of different stem cell sources (reviewed by Peters and colleagues elsewhere in this issue), and the development of nonmyeloablative conditioning that is associated with delayed onset aGVHD. These advancements have made the distinction between acute and chronic GVHD based on time of onset no longer accurate. Therefore, it is preferable to recognize aGVHD by the clinicopathologic constellation of combinations of inflammatory dermatitis, enteritis, and hepatitis, which reflects T cell activation with generation of cytotoxic lymphocytes and inflammatory cytokines that cause tissue damage. Chronic GVHD (cGVHD) is now similarly recognized without reference to time after HSCT by the presence of diagnostic or distinct cGVHD manifestations that resemble autoimmune diseases; cGVHD is reviewed by Baird and colleagues in this issue and elsewhere. Thus, for example, secretory diarrhea or erythematous maculopapular dermatitis following a relapsing or indolent course is classified as late persistent aGVHD or cGVHD (with overlap syndrome) if classic manifestations of cGVHD are also present. It remains to be determined whether the type or duration of immunosuppressive therapy should differ based on these clinical distinctions.
GVHD Classification
The severity of aGVHD is determined by the degree (or stage) of involvement in each of the main target organs (skin, liver, and upper and lower gastrointestinal (GI) tract) based on accepted criteria that primarily include the extent of rash, magnitude of hyperbilirubinemia, volume of diarrhea, and presence of nausea ( Table 1 ). Various combinations of skin, liver, and GI involvement are then used to assign an overall GVHD severity or grade, as per the modified Glucksberg criteria (Grades I–IV) most commonly or by the International Bone Marrow Transplant Registry (IBMTR) Index (Grades A–D) less commonly ( Table 2 ).
| Stage 0 | Stage 1 | Stage 2 | Stage 3 | Stage 4 | |
|---|---|---|---|---|---|
| Skin | No rash | Rash <25% BSA | 25%–50% | >50% generalized erythroderma | Plus bullae and desquamation |
| Gut | Adult: <500 mL/d Child: <10 mL/kg/d | Adult: 500–1000 mL/d Child: 10–19.9 mL/kg/d | Adult: 1001–1500 mL/d Child: 20–30 mL/kg/d | Adult: >1500 mL/d Child: >30 mL/kg/d | Severe abdominal pain ± ileus, flank blood, or melena |
| Upper GI | – | Severe nausea/vomiting | – | – | – |
| Liver | Bilirubin ≤2 mg/dL | 2.1–3 mg/dL | 3.1–6 mg/dL | 6.1–15 mg/dL | >15 mg/dL |
