Acquired aplastic anemia in children

Abstract

This article provides a practice-based and concise review of the etiology, diagnosis, and management of acquired aplastic anemia in children. Bone marrow transplantation, immunosuppressive therapy, and supportive care are discussed in detail. The aim is to provide the clinician with a better understanding of the disease and to offer guidelines for the management of children with this uncommon yet serious disorder.

Keywords: Acquired aplastic anemia; Bone marrow failure; Bone marrow transplant for severe aplastic anemia in children; Immune-mediated aplastic anemia; Immunosuppressive therapy for severe aplastic anemia in children.

Figure 1

Bone marrow aspirate and biopsy from a patient with acquired AA. Hematopoietic elements are greatly reduced, and there is replacement of marrow space with adipose tissue. Focal islands of left-shifted erythropoiesis (Fig 1: H&E stain, original magnification ×20; Inset: H&E stain, original magnification ×200). (Courtesy of Dr Michele E. Paessler, DO, Pathology, The Children’s Hospital of Philadelphia.)

Figure 2

Schematic representation of a relationship between genetic mutations, disease penetrance, and gene-environment interaction in the pathogenesis of bone marrow failure. Mutations with a high disease penetrance almost always cause disease, i.e. mutations in the Fanconi Anemia genes (FANC), in the SBDS gene causing Shwachman Diamond Syndrome, or in DKC1 causing X-linked Dyskeratosis Congenita. In contrast, mutations in genes with low disease penetrance may not manifest as clinically apparent bone marrow failure, examples include mutations in the TERT gene responsible for autosomal dominant Dyskeratosis Congenita or in certain DBA genes responsible for Diamond Blackfan Anemia. Genetic polymorphisms associated with AA don’t cause disease in the majority of carriers but, in combination with other modifier genes and the appropriate environmental insult, may contribute to the development of AA. Examples are HLA-DR2 in adult AA and HLA-B14 in pediatric AA or GSTT1 gene deletions.^,,,

Figure 3

Current evidence suggests that acquired AA results from the aberrant activation of one or more auto-reactive T cell clones due to alteration of antigens presented by the Major Histocompatibility Complex (MHC) on the surface of Antigen Presenting Cells (APC). This antigen alteration is triggered by viral infection, chemical exposure, or genetic mutation, and leads to the inappropriate activation of antigen-specific effector T cells and decreased activity of regulatory T cells, which normally serve to prevent auto-immunity. T cell activation leads to IL-2-driven expansion and differentiation of T cells into effector and memory T cells. These pro-inflammatory T cells produce a variety of cytokines, including FAS Ligand (FASL), interferon-γ (IFN-γ), and Tumor Necrosis Factor α (TNFα), which 1) induce HSC apoptosis and 2) alter gene regulation and decrease protein synthesis to prevent HSC cell cycling, ultimately leading to bone marrow failure. Immune suppression therapy disrupts T cell-driven HSC destruction by inhibiting T cell responses at several points along this pathway.^,

Figure 4

Flow diagram for antimicrobial prophylaxis and empiric fever management for patients with severe aplastic anemia currently used at the Comprehensive Bone Marrow Failure Center CHOP/UPENN. PJP, Pneumocystis jiroveci pneumonia. (Courtesy of Drs. Talene Metjian PharmD, Brian T. Fisher, DO MSCE, Infectious Diseases, and Shefali Parikh, MD, Hematology, The Children’s Hospital of Philadelphia)

Figure 5

Treatment algorithm for AA and sAA. MRD, matched related donor; hATG, horse antithymocyte globulin; rATG, rabbit antithymocyte globulin, CSA cyclosporine, URD unrelated donor; BMT bone marrow transplant; IST, immune suppressive therapy.