Hemophagocytic Lymphohistiocytosis

Abstract

Context.— Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder of immune regulation that can eventually result in end-organ damage and death. HLH is characterized by uncontrolled activation of cytotoxic T lymphocytes, natural killer cells, and macrophages that can lead to a cytokine storm. The diagnosis of HLH is often challenging due to the diverse clinical manifestations and the presence of several diagnostic mimics. The prognosis is generally poor, warranting rapid diagnosis and aggressive management. Objective.— To provide a comprehensive review of the pathogenesis, clinical features, diagnosis, and management of HLH. Data Sources.— Peer-reviewed literature. Conclusions.— HLH is a condition where a complete understanding of the pathogenesis, early diagnosis, and proper management has an important role in determining patient outcome. Genetic mutations causing impairment in the function of cytotoxic T lymphocytes and natural killer cells have been identified as the root cause of familial HLH; however, the specific pathogenesis of acquired HLH is unclear. The HLH-2004 protocol used in the diagnosis of HLH was originally developed for the pediatric population. The HLH-2004 protocol still forms the basis of the diagnosis of HLH in adults, although its use in adults has not been formally validated yet. Treatment of HLH is primarily based on the HLH-94 protocol, which involves suppressing the inflammatory response, but the treatment needs to be modified in adults depending on the underlying cause and comorbidities.

A Rare Case of Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome in Settings of Etanercept Use and Epstein-Barr Virus Infection

“…If the patient does not respond to initial therapy, hematopoietic cell transplant (HCT) is considered, as well as the continuation of initial induction therapy past the eight weeks. Some of the indications for HCT include homozygous/compound HLH gene mutations, lack of response to initial therapy, CNS involvement, and presence of hematologic malignancy [8]. Prognosis is poor, with survival approaching 58% in adults and two-month survival in those with an inherited mutation without receiving treatment due to progressive multiorgan failure [9].…”

Is COVID-19-associated cytokine storm distinct from non-COVID-19 secondary hemophagocytic lymphohistiocytosis?

“…HLH is a highly fatal condition characterized by dysregulated hyperactivation of lymphocytes and macrophages leading to hyperferritinemia, hyperinflammatory cytokine storm, and multiorgan failure. 4 Without treatment, HLH mortality rate approaches 100%. 25 As a disorder of macrophages, HLH is categorized with other histiocytic (dendritic cell or monocyte/macrophage) disorders (Table 1), giving rise to the eponymous name.…”

“…HLH-directed therapy should be initiated if the suspicion remains high despite not meeting all five criteria. 4 Other features supporting an HLH diagnosis include hyperbilirubinemia, hepatomegaly, transaminitis, elevated lactate dehydrogenase (LDH), and D-dimer levels. 4…”

“…4 Other features supporting an HLH diagnosis include hyperbilirubinemia, hepatomegaly, transaminitis, elevated lactate dehydrogenase (LDH), and D-dimer levels. 4…”

“…Finally, a recognized form of CS/CRS is HLH, which is defined by specific clinical and pathologic criteria and has an immunobiological phenotype that is rapidly emerging from research. 3,4 Severe COVID-19 pneumonia 5,6 leading to acute respiratory distress syndrome (ARDS) 7 can lead to systemic hyperinflammation [8][9][10][11] and CS/CRS. 12 Profiling of cases has previously documented elevated levels of interferongamma-induced protein 10 (IP-10), monocyte chemotactic protein 3 (MCP-3), and interleukin-1 receptor antagonist (IL-1ra), which are associated with disease severity and fatality.…”