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Hemophagocytic lymphohistiocytosis

Definition
HLH is a severe hyperinflammatory syndrome caused by aberrant activation of macrophages and cytotoxic T cells.
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Pathophysiology
Primary HLH is due to genetic abnormalities (including perforin and syntaxin mutations), while secondary HLH is due to underlying conditions such as infections (notably, EBV, CMV, parvovirus B19, HIV, and HHV-6), autoimmune/rheumatologic disease, malignancy, or metabolic conditions. Secondary HLH caused by rheumatologic disease is often termed "macrophage activating syndrome," and has been reported in association with adult-onset Still's disease, polyarteritis nodosa, mixed connective tissue disease, pulmonary sarcoidosis, systemic sclerosis, Sjögren's syndrome, and SLE.
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Epidemiology
The incidence of HLH is estimated at 0.1 cases per 100,000 person-years.
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Disease course
Key clinical manigestations include fever, hepatomegaly or splenomegaly, and bi- or trilineage cytopenias. In addition, elevated liver enzymes, hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia are commonly seen.
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Prognosis and risk of recurrence
Mortality has been reported to vary from 8-22% in rheumatologic HLH to 18-24% in EBV associated HLH.
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Key sources
The following summarized guidelines for the evaluation and management of hemophagocytic lymphohistiocytosis are prepared by our editorial team based on guidelines from the Histiocyte Society (HS 2019).
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Guidelines

1.Screening and diagnosis

Indications for testing: test for HLH in critically ill patients with persistent fever, cytopenias, and organomegaly, particularly in confirmed or presumed cases of sepsis, sepsis-like syndromes, and/or evolving multiorgan failure.
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  • Diagnostic criteria

2.Classification and risk stratification

Classification
As per HS 2019 guidelines:
Recognize that primary and secondary hemophagocytic syndromes, including macrophage activating syndrome, are hyperferritinemic, hyperinflammatory syndromes with a common terminal pathway but with different pathogenetic roots.
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Recognize that malignancy-associated HLH may present as one of two distinct entities:
malignancy-triggered HLH, as a presenting feature of the malignancy at diagnosis or at relapse
HLH during chemotherapy, in most cases induced by infections
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3.Diagnostic investigations

Evaluation for etiology: conduct a meticulous search for an underlying trigger in patients with HLH, including occult malignancies, despite ongoing HLH treatment.
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  • Genetic testing

4.Medical management

General principles
As per HS 2019 guidelines:
Recognize that the variable severity of HLH, including macrophage activating syndrome, demands graded intensity and length of treatment. Tailor treatment to control hyperinflammation and treat identified disease triggers.
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Recognize that treatment of macrophage activating syndrome is different from that recommended for HLH, as a result of partial pathogenetic diversity.
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More topics in this section

  • HLH-94 regimen

  • Management of HLH due to intracellular infections

  • Management of refractory/relapsing HLH