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.
Proposed HLH 2004 diagnostic criteria include the following (at least 5 of 8 required):
- Fever (> 7 days)
- Splenomegaly (> 3 cm below costal margin)
- 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)
- Hypertriglyceridemia (fasting levels > 3 mmol/L) and/or hypofibrinogenemia (< 1.5 g/L)
- Tissue sample (from bone marrow, liver, or lymph nodes) demonstrating macrophage phagocytosis of erythrocytes, platelets, leukocytes, and precursor cells
- Low/absent NK cell activity
- Hyperferritinemia (> 500 μg/L)
- High levels of soluble IL-2 receptor
Left untreated, HLH is fatal, especially in the familial forms.
Immunocompromised Patient Considerations:
HLH can be triggered by immunodeficient states such as HIV infection.