Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)

Updated: Oct 18, 2017
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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Overview

Background

Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disease of normal but overactive histiocytes and lymphocytes that commonly appears in infancy, although it has been seen in all age groups. Fever, hepatosplenomegaly, pancytopenia, lymphadenopathy, and rash often comprise the initial presentation. Cutaneous involvement occurs in as many as 65% of patients. [1] Varied skin manifestations of hemophagocytic lymphohistiocytosis are noted, including erythroderma, generalized purpuric macules and papules, and morbilliform eruptions. Detection of cutaneous involvement can assist in the initial diagnosis of hemophagocytic lymphohistiocytosis and potentially signify recurrences.

Primary hemophagocytic lymphohistiocytosis (ie, familial erythrophagocytic lymphohistiocytosis [FEL]), an inherited form of hemophagocytic lymphohistiocytosis syndrome, is a heterogeneous autosomal recessive disorder found to be more prevalent with parental consanguinity. Secondary hemophagocytic lymphohistiocytosis (ie, acquired hemophagocytic lymphohistiocytosis) occurs after strong immunologic activation, such as that which can occur with systemic infection, immunodeficiency, or underlying malignancy. Both forms are characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and hematologic alterations and death in the absence of treatment. [2]

The history of this disorder, its molecular basis, and treatment options are noteworthy. [3] Almost 60 years has passed since Scottish pediatricians James Farquhar and Albert Claireaux, both of the University of Edinburgh, noticed the familial recurrence of this disorder affecting male and female siblings aged 2 months, causing fever, cytopenia, hepatosplenomegaly, and rapidly death despite treatment with antibiotics and steroids. [4]

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Pathophysiology

The pathological hallmark of this disease is the aggressive proliferation of activated macrophages and histiocytes, which phagocytose other cells, namely RBCs, WBCs, and platelets, leading to the clinical symptoms. The uncontrolled growth is nonmalignant and does not appear clonal in contrast to the lineage of cells in Langerhans cells histiocytosis (histiocytosis X). The spleen, lymph nodes, bone marrow, liver, skin, and membranes that surround the brain and spinal cord are preferential sites of involvement. [5] This disorder may be viewed as a highly stimulated, but ineffective, immune response to antigens, which results in life-threatening cytokine storm and inflammatory reaction. [6]

Over the past 2 decades, the underlying pathophysiology of hemophagocytic lymphohistiocytosis has been characterized, although the processes are not entirely understood. A current accepted theory involves an inappropriate immune reaction caused by proliferating and activated T cells associated with macrophage activation and inadequate apoptosis of immunogenic cells. [7] Although the precise mechanism remains unclear, many research teams propose convincing pictures for the role of perforin and natural killer (NK) cells in the hemophagocytic lymphohistiocytosis subtypes. [8, 9, 10]

Perforin or pore-forming protein (PFP), gene map location 10q22, is one of the major cytolytic proteins of granules contained in cytotoxic cells. [11] When activated by a challenge, NK cells release granules that contain perforin and granzymes, which form pores in the target cell membrane and cause osmotic lysis and protein degradation, respectively. Additionally, the endocytotic and exocytotic mechanisms may also be affected. [12] Patients with perforin deficiency may have impaired defenses against intracellular pathogens and cancers, as has been demonstrated in animal models.

Although the mechanism is yet to be determined, decreased NK cell activity results in increased T-cell activation and expansion, with resulting production of large quantities of cytokines, including interferon gamma (IFNg), tumor necrosis factor-a (TNF–a), and granulocyte-macrophage colony-stimulating factor (GM-CSF). This causes sustained macrophage activation and tissue infiltration as well as production of interleukin-1 (IL–1) and interleukin-6 (IL-6). The resulting inflammatory reaction causes extensive damage and the associated symptoms. [13]

While mutations in STX11 are said to be responsible for much of the familial hemophagocytic lymphohistiocytosis in the Middle East, one survey found such mutations in only 1% of North American patients. [14]

One study showed a vulnerability to Epstein-Barr virus infection in Korean children (Koh et al). [15] Epstein-Barr virus, the pathogen that most commonly triggers infection-associated hemophagocytic lymphohistiocytosis, also infects CD8(+) T cells in EBV-associated hemophagocytic lymphohistiocytosis. [16, 17] Demonstrating these cells by their immunophenotypic characteristics may aid in the diagnosis of Epstein-Barr virus associated-hemophagocytic lymphohistiocytosis. One should also consider ehrlichiosis as a possible trigger of hemophagocytic lymphohistiocytosis. [18]  However, in a Brazilian sampling of 50 patient, 34 adults and 16 children, Epstein-Barr virus infection was found to be less common in adults compared with children. [19]

The familial form is a rare autosomal recessive disorder that has been classified into 6 different types based on genetic linkage analysis and chromosomal localization; 5 specific genetic defects have been identified, which account for approximately 90% of all patients. [20] Type 1 is due to a gene defect on chromosome 9, type 2 is due to mutations in the perforin gene, type 3 is due to mutations in the Munc-13-4 (UNC13D) gene, type 4 is due to mutations in the syntaxin 11 (STX11) gene, and type 5 is due to mutations in the gene encoding syntaxin binding protein 2 (STXBP-2).

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Epidemiology

Frequency

International

Incidence is reported to be 1.2 cases per million persons per year. However, unpublished observations estimate that the figures have slightly increased over time because of improved detection. [21] This amounts to 1 case per every 50,000 births. [22]

Perforin mutations account for approximately 20% of cases of FEL, with a somewhat higher prevalence (30%) in children of Turkish descent. Chromosome arm 9q mutations account for approximately 10% of familial cases; the remainder of FEL cases are caused by mutations in as yet unidentified genes. [23]

Mortality/Morbidity

Familial hemophagocytic lymphohistiocytosis is uniformly fatal if not treated; the median survival time reported in various studies is 2-6 months after diagnosis. The historical series collected by the International Hemophagocytic Lymphohistiocytosis Registry reports a less than 10% probability that the patient survives for 3 years. [24] Even with treatment, only 21-26% can be expected to survive 5 years. Remission is always temporary, as the disease inevitably returns. Bone marrow transplant is the only hope for cure. One study found that 50% of deaths from FEL were due to invasive fungal infections, which are probably underdiagnosed. [22] The outcomes of secondary hemophagocytic lymphohistiocytosis vary.

Race

Hemophagocytic lymphohistiocytosis has not been epidemiologically shown to have a predilection for persons of any race. A sample of European countries, including Sweden, England, and Italy, has reported similar statistical incidences as mentioned above. [13]

Sex

The disease has an equal distribution among males and females.

Age

The age of onset is usually in people younger than 1 year for the familial form but can be later for the secondary sporadic form, usually after age 6 years. [7] Although the familial form of the disease frequently affects infants from birth to age 18 months, familial forms have been reported in individuals as old as 8 years, and adult onset has been reported. At this point, no criteria for age have been established, and an upper age limit does not exist. [22]

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