MORPHOLOGYThenodalchangesincat-scratchdiseasearequitecharacteristic.Initiallysarcoidlikegranulomasform,butthesethenundergocentralnecrosisassociatedwithaninfiltrateofneutrophils.Theseirregular stellate necrotizing granulomas aresimilarinappearancetothoseseeninalimitednumberofotherinfections,suchaslymphogranulomavenereum.Themicrobeisextracellularandcanbevisualizedwithsilverstains.Thediagnosisisbasedonahistoryofexposuretocats,thecharacteristicclinicalfindings,apositiveresultonserologictestingforantibodiestoBartonella, andthedistinctivemorphologicchangesinthelymphnodes.
HLH is an uncommon disorder in which a viral infection or other proinflammatory exposures trigger activation of macrophages throughout the body, leading to phagocytosis of blood cells and their precursors, cytopenias, and symptoms related to systemic inflammation and organ dysfunction. Inherited defects in several genes that regulate the function of immune cells are associated with a greatly elevated risk of HLH. The involved genes and proteins are diverse, but they share a common feature in that they are required for the cytolytic function of CD8+ T cells and NK cells. Owing to this defect in “killer lymphocytes,” cytotoxic lymphocytes are unable to kill their targets (e.g. virus infected cells) and remain engaged with targeted cells for longer than normal periods of time, leading to excessive release of cytokines, such as interferon gamma, that activate macrophages. The unbridled macrophage activation results in the release of toxic levels of additional pro-inflammatory cytokines, such as TNF and IL-6, producing signs and symptoms that closely resemble those associated with sepsis and other conditions that lead to the systemic inflammatory response syndrome (SIRS) (Chapter 4).
HLH occurs in several distinct settings. It is most common in infants and young children with homozygous defects in genes that are required for cytotoxic lymphocyte function, such the gene PRF1, which encodes perforin, an essential component of cytotoxic granules. In this setting the trigger may be some normally trivial childhood viral infection. Other times, HLH arises in older male children and adolescents with X-linked lymphoproliferative disorder, in which the trigger is EBV infection. In those affected, inherited defects in a signaling molecule called SLAM-associated protein (SAP) leads to inefficient killing of EBV-infected B cells. HLH also may complicate other systemic inflammatory disorders, such as rheumatologic conditions. At least a subset of these individuals have heterozygous defects in genes required for cytotoxic lymphocyte function, creating a genetic background that increases the likelihood of HLH. Finally, HLH may be seen as a secondary phenomenon in patients with peripheral T cell lymphomas. The precise mechanism in this context is uncertain; aberrant cytokine production by malignant T cells leading to dysregulation of non-neoplastic cytotoxic lymphocytes is suspected.