1 | Introduction
Hemophagocytic lymphohistiocytosis is an aggressive and life-threatening
condition with excessive activation of cytotoxic T lymphocytes, natural
killer (NK) cells, and macrophages resulting in hypercytokinemia and
immune-mediated damage to multiple organ systems. Primary (driven via
underlying genetic mutations or secondary (driven from a malignant,
infectious, or autoimmune stimulus without an identifiable underlying
genetic trigger).(1) Progress has been made regarding the
pathophysiology of HLH over the past decade. However, diagnosis of HLH
remains with many dilemmas because of the heterogeneous nature of the
disease.(2)
The guidelines for hemophagocytic lymphohistiocytosis describe the
various symptoms that can be considered for a clinical diagnosis. If
five of the following eight symptoms are present, then a clinical
diagnosis can be made. These eight symptoms are fever; an abnormally
large spleen (splenomegaly); low red cell, white cell, or platelet
levels (cytopenias); abnormally high levels of a type of fat called a
triglyceride in the blood (hypertriglyceridemia) or low levels of a
specific blood-clotting protein (hypofibrinogenemia); destruction of
blood cells by macrophages (hemophagocytosis) in the bone marrow; low or
absent natural killer cell activity; abnormally high levels in the blood
of a protein that binds to iron (ferritinemia); and elevated soluble
interleukin-2 receptor (sCD25), a specialized protein that builds up in
the blood when the immune system is stimulated.
Excessive monocyte activation in HLH could be caused by high amounts of
activating cytokines. High levels of interferon (IFN), soluble
interleukin-2 receptor, tumor necrosis factor (TNF), interleukin-1, and
interleukin-6 have been found, implying that T-helper cells are
elaborating activating cytokines or that poorly regulated or
inappropriate Th1 responses to intracellular pathogens are to blame.
Although the details of immunological protective mechanisms against
rickettsial infections, such as cytokine activation, are unknown,
macrophages and T-cells are thought to play a key role in rickettsial
infection protection and the emergence of HLH. HLH is caused by a
variety of viruses, including CMV, Epstein-Barr virus (EBV), and human
herpesvirus-6, as well as collagen-vascular disorders and malignancies,
including T-cell lymphomas.(3)