Pediatric hemophagocytic syndromes: a diagnostic and therapeutic challenge

Abstract

Pediatric hemophagocytic syndrome (HS) is a severe and often fatal clinical disorder. This syndrome is frequently unrecognized, and thus, affected children may receive suboptimal management, leading to an increase in mortality. The purpose of this review is to provide a clinical guide to (1) the recognition of HS based on clinical, biologic, and pathologic features; (2) the identification of the primary cause of HS in a given affected child; and (3) the initiation of effective treatment in a timely manner.

Figure 1

Schematic overview of antigen specific CD8+ T-cell response in a normal individual (A) and in a patient with hemophagocytic syndrome (B). In response to an infectious trigger, antigen-specific CD8⁺ T cells transiently undergo massive expansion, use cell-mediated cytolysis, and produce interferon-γ (IFN-γ). After pathogen clearance, this immune response is self-limiting and most cells die, leaving a reduced number of memory T and B cells. During the course of hemophagocytic syndrome, uncontrolled expansion of antigen-specific effectors occurs. Activated lymphocytes secrete high levels of INF-γ and induce a feedback loop on macrophage and T cells, which continuously activate each other and expand. High levels of inflammatory cytokines are secreted, including IFNγ, tumour necrosis factor-α, interleukin (IL)-1, IL-6, and IL-18. Activated macrophages phagocytose bystander hematopoietic cells (hemophagocytosis). Activated lymphocytes and macrophages infiltrate various organs, resulting in massive tissue necrosis and organ failure.

Figure 2

Cytotoxic granules in wild-type cytotoxic T lymphocytes (CTLs) and in CTLs from patients with genetic defects. A, Illustrations of the distribution of cytotoxic granules on microtubules (lines) in a resting human CTL (left panel). Perforin and granzyme are represented as red and green circles inside granules; one granule of each only is shown for clarity. After a CTL encounters a target cell, cytotoxic granules polarize and move along microtubules (middle panel) to the microtubule organizing centre (in blue), which migrates to the immunologic synapse and induces apoptosis of the target cell after the endocytosis of cytotoxic granules in its cytoplasm (right panel). B, Illustration of images of CTLs from patients lacking Lyst (Chédiak-Higashi syndrome), MUNC13-4 (FHL3), or RAB27A (Griscelli syndrome 2) conjugated with target cells.

Figure 3

Schematic representation of cytotoxic granule exocytosis and target killing following target recognition by cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells) Recognition of a peptide-major histocompatibility complex class I molecule presented by a target cell induces activation of cytotoxic lymphocytes (CTLs and NK cells). After cell conjugate formation, activated lymphocytes polarize their lytic granules toward the cell-to-cell contact, organized as an immunologic synapse. RAB27A is expected to promote the terminal transport and/or the docking step of the cytotoxic granules at the immunologic synapse. For its function, RAB27A potentially associates with unknown effectors and with MUNC13-4. MUNC13-4 functions as a priming factor, allowing cytotoxic granules to reach a fusion-competent state before membrane fusion and granule secretion occur. In 30% of patients with familial hemophagocytic lymphohistiocytosis (FHL), cytotoxic granules are defective in their functional perforin content (FHL2); in another 30% of the patients, cytotoxic granules are defective in their priming state and thus secretion (FHL3). Defective RAB27A in patients with Griscelli syndrome 2 impairs terminal transport and thus exocytosis of the lytic granule contents. X-linked lymphoproliferation and polymerization of perforin are represented with a question mark because there is no experimental proof that they act as represented in this scheme.

Figure 4

Illustration of hemophagocytosis and the most prominent extrahematologic features of Griscelli and Chédiak-Higashi syndromes. A, Hemophagocytosis in the bone marrow of a patient with familial hemophagocytic lymphohistiocytosis; arrow indicates an activated macrophage that has ingested several red blood cells. B, Partial view of the head of a child with Griscelli syndrome 2, shown to emphasize the ashengrey colour of hair. Electron microscopy images of a normal hair (left panel) and a hair of a person with Griscelli syndrome (right panel) are shown below; arrows indicate clumps of melanin specific for this disease. A defect in any of the proteins (myosin Va, RAB27A, or melanophilin) leads to identical pigmentary dilution in the three forms of Griscelli syndrome and their mouse models. C, Blood smear taken from a patient with Chédiak-Higashi syndrome. Arrows indicate large granules present in all cell lineages that orient the diagnosis toward Chédiak-Higashi syndrome.