Hemophagocytic Lymphohistiocytosis and Other Hemophagocytic Disorders

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Hemophagocytic disorders result when critical regulatory pathways responsible for the natural termination of immune/inflammatory responses are disrupted or overwhelmed. Hemophagocytic disorders reflect pathologic defects that alter the normal crosstalk between innate and adaptive immune responses, and compromise homeostatic removal of cells that are superfluous or dangerous to the organism. Although hemophagocytic disorders are considered rare, increased awareness of these conditions has led to more frequent diagnoses, more rapid initiation of life-saving treatments, and new insights into the molecules and pathways involved in natural immune down-regulation. Furthermore, improved understanding of the immunologic abnormalities revealed by hemophagocytic disorders informs potential new treatments for life-threatening multisystem organ dysfunction related to sepsis in the intensive care unit setting and severe cases.

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Pathogenesis of hemophagocytic lymphohistiocytosis and other histiocytic disorders

HLH is characterized by multisystem inflammation, a reactive process resulting from prolonged and intense activation of antigen-presenting cells (macrophages, histiocytes) and CD8 + T cells, and excessive proliferation and ectopic migration of T cells.

Normal functions of histiocytes, a major population of cells within the innate immune system, include phagocytosis, antigen presentation, and activation of the adaptive immune system through contact and cytokine signaling.

Abnormalities in the

Clinical presentation of hemophagocytic lymphohistiocytosis

Until recently, it was widely believed that the symptoms of familial HLH (also referred to as FHL in the literature) generally arose during infancy and early childhood. With the more widespread availability of genetic testing, it is apparent that the first significant episode of HLH can occur throughout life [7], [8], including in utero [9]. HLH should be considered as part of the differential diagnosis of nonimmune hydrops fetalis [9]. In infants, significant symptomatic overlap has been

Genetics of hemophagocytic lymphohistiocytosis and other histiocytic disorders

To date, all described genetic defects associated with HLH and other histiocytic disorders appear to be related to one another in the pathway of granule-mediated cytotoxicity. These genetic defects interrupt the mechanisms responsible for triggered apoptosis (mediated by cytotoxic cells on the target cell) or activation-induced apoptosis (putative suicide of activated T cells). The first gene linked to HLH was perforin [14], a soluble, pore-forming cytolytic protein synthesized in cytolytic

Hemophagocytic disorders associated with other immunodeficiencies and infections

The clinical syndrome of HLH has occasionally been observed in patients who have other underlying primary immunodeficiencies, including some with restricted T repertoires and function, such as the del22q11 syndrome, or DiGeorge syndrome [38], and severe combined immunodeficiency. Sporadic cases of hemophagocytic complications in patients who have chronic granulomatous disease [39] and X-linked agammaglobulinemia, and the X-linked NEMO [40] defect have also been reported. In these case reports,

Hemophagocytic disorders associated with autoimmune disorders

The most commonly recognized association of hemophagocytic syndrome with rheumatoid disorders is the macrophage activation syndrome (MAS) [56], [57]. MAS, most often associated with systemic onset juvenile inflammatory arthritis (soJIA), can be the first presenting feature of soJIA. MAS, and particularly recurrent MAS, bears a close resemblance symptomatically and immunologically to HLH. Many cases of MAS are characterized by low NK-cell function and deficient perforin expression in cytotoxic

Hemophagocytic disorders associated with malignancies

The association of hemophagocytic complications with malignancies, typically lymphoid malignancies, including T-cell and NK-cell tumors, peppers the literature [44]. In many cases, HLH represents a proximate life-threatening complication of the tumor or its therapy, and is associated with a poor prognosis. Until recently, these malignancies and hemophagocytic reactions have been viewed as side effects, perhaps the consequence of abnormal cytokine generation by the malignant cells. However, more

Diagnosis of hemophagocytic lymphohistiocytosis

To assist with the rapid diagnosis of HLH, the Histiocyte Society has developed a set of diagnostic guidelines that encompass clinical and laboratory findings (Box 1) [2]. In the absence of a family history or specific genetic diagnosis, an assemblage of five or more of the eight diagnostic criteria are needed for a provisional diagnosis of HLH and initiation of therapy. These include persistent fevers without clear cause, splenomegaly, bicytopenia, hypertriglyceridemia or hypofibrinogenemia,

Treatment of hemophagocytic lymphohistiocytosis and related disorders

A retrospective review of HLH 25 years ago described mean survival of less than a month after symptomatic onset and 5% overall survival at 1 year after diagnosis [77]. Today, effective initial therapy of HLH consists of combinations of proapoptotic chemotherapy and immunosuppressive drugs targeting the hyperactivated T cells and histiocytes. Currently, definitive treatment of, and a potential cure for, FLH is only achieved by hematopoietic cell therapy (HCT). Projected survival rates, 5 years

Why is the disease named hemophagocytic lymphohistiocytosis versus macrophage activation syndrome or lymphohistiocytic activation syndrome?

Hemophagocytosis (typically sought on bone marrow biopsy) is not a universal finding of this group of disorders, even in the most fulminant forms. Indeed, some controversy exists as to whether the phenomenon recognized by the findings of hematopoietic cells engulfed by activated monocyte/macrophages represents phagocytosis, pinocytosis, or some related mechanism. Perhaps in the future a new name for this group of disorders will be adopted.

How common is natural killer cell dysfunction in hemophagocytic lymphohistiocytosis?

The HLH 2004 protocol, developed by the working party of

Acknowledgments

Many colleagues must be thanked for the ideas and research incorporated into this article. First and foremost are the patients and families who choose to trust and teach us. At Cincinnati Children's Hospital, I am fortunate to work with physician scientists working on hemophagocytic disorders, including Jack Bleesing, MD, PhD, Michael Jordan, MD, Kim Risma, MD, PhD, Janos Sumegi, MD, PhD, Rebecca Marsh, MD, and Kejian Zhang, MD, MBA, and Judith Johnson, MS, genetic counselor. Within the

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      Citation Excerpt :

      In addition, it is known that normal ranges of sIL-2R levels are different according to patients' ages, the levels being very high in infants and quite low in teens and adults. The results may vary according to methods used for analysis, as well [6,20]. Therefore, normal ranges according to ages should be determined.

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