Hemophagocytic lymphohistiocytosis (HLH), also known as histiocytic medullary reticulosis, macrophage activation syndrome, and familial hemophagocytic lymphohistiocytosis (for inherited forms), is a relatively uncommon hemophagocytic syndrome. HLH affects all age groups, but the majority of cases are in infants (often younger than 1 year old) and young children.

HLH tends to affect the bone marrow, spleen, lymph nodes, liver, central nervous system, and skin. Up to 65% of patients have nonspecific cutaneous involvement ranging from a transient generalized morbilliform rash to petechiae, purpuric macules, or papules to erythroderma. Without treatment, HLH can be rapidly fatal.

It is classified into primary (familial) and secondary (acquired, sporadic) forms:

• Familial hemophagocytic lymphohistiocytosis (FHL) is inherited in an autosomal recessive pattern; approximately 24% of 122 cases reviewed by the FHL Study Group of the Histiocyte Society had a history of parental consanguinity. Estimated incidence of FHL is 1.2 per million in children under the age of 15; 70%-80% of FHL cases present before 1 year of age. Up to 80% of FHL cases are caused by mutations in 1 of 3 genes (encoded protein in parentheses): PRF-1 (perforin, most common), UNC13D (Munc13-14), and STX-11 (syntaxin-11). Both perforin and Munc13-14 proteins are involved in host response to infection, while the exact role of syntaxin-11 has yet to be determined. 
• Secondary HLH may occur sporadically or in the context of FHL. It is thought to be related to immune stimulation by infection (eg, Epstein-Barr virus [EBV], human herpes simplex virus [HSV], coxsackievirus B, echovirus, other human herpesviruses, tuberculosis, and other viral, fungal, and parasitic infections), malignancy (eg, acute lymphoblastic leukemia, acute myelogenous leukemia, and lymphomas), collagen vascular disease (eg, juvenile rheumatoid arthritis), and immunodeficiency (eg, human immunodeficiency virus infection [HIV]). EBV-associated HLH may present similarly to a T-cell lymphoma. Human HSV-, coxsackievirus B-, and echovirus-associated HLH should be a consideration in neonates. HLH has also been reported in association with Chediak-Higashi, Griscelli, and rare X-linked lymphoproliferative syndromes.

The pathophysiology behind both primary and secondary HLH is T-cell immune dysregulation. While the exact mechanism is unknown, the dysregulatory process results in an overproduction of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma), and various interleukins (IL). These molecules activate T-cells, macrophages, and histiocytes. This disrupts the mechanisms that regulate apoptosis. Natural killer (NK) cells, particularly in FHL, are absent or reduced. Under normal circumstances, NK cells (which have granules containing perforin and granzymes that disrupt target cell membrane integrity) participate in natural cell death.

Proposed HLH 2004 diagnostic criteria include the following (at least 5 of 8 required):

1. Fever (> 7 days)
2. Splenomegaly (> 3 cm below costal margin)
3. Blood cell dyscrasia (> 2 of 3 lineages – hemoglobin < 9.0 g/dL, platelets < 100 000/L, absolute neutrophils < 1000/μL – in absence of hypocellular marrow)
4. Hypertriglyceridemia (fasting levels > 3 mmol/L) and/or hypofibrinogenemia (< 1.5 g/L)
5. Tissue sample (from bone marrow, liver, or lymph nodes) demonstrating macrophage phagocytosis of erythrocytes, platelets, leukocytes, and precursor cells
6. Low/absent NK cell activity
7. Hyperferritinemia (> 500 μg/L)
8. High levels of soluble IL-2 receptor

Other common clinical signs include hepatomegaly, lymphadenopathy, nonspecific cutaneous eruptions, and neurological abnormalities.

Left untreated, HLH is fatal, especially in the familial forms.

Immunocompromised Patient Considerations:
HLH can be triggered by immunodeficient states such as HIV infection.