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)