What is Hemophagocytic Lymphohistiocytosis (HLH)?
HLH is a life-threatening hyperinflammatory syndrome characterized by uncontrolled activation of cytotoxic T lymphocytes, NK cells, and macrophages, resulting in a cytokine storm that causes progressive multi-organ damage and, without treatment, leads to death from multiple organ failure. 1, 2
Core Pathophysiology
HLH represents a severe immune dysregulation where the body loses its ability to terminate an inflammatory response. 2 The syndrome arises through two distinct pathways:
Primary (Genetic) HLH: Results from hereditary defects in perforin-mediated cytotoxicity (familial HLH types 2-5, Griscelli syndrome type 2, X-linked lymphoproliferative syndromes), most commonly presenting in children but can occur in adolescents and young adults. 1, 2
Secondary (Acquired) HLH: Represents immune system failure to restrict stimulatory effects of various triggers—infections (especially EBV and CMV), malignancies (particularly T-cell/NK-cell lymphomas, DLBCL, Hodgkin lymphoma), autoimmune disorders, or chemotherapy-induced immunosuppression. 1, 2
Both pathways converge on a common terminal pathway: sustained aberrant activation of CD8+ T cells and macrophages produces massive hypercytokinemia, causing tissue infiltration by activated lymphocytes and histiocytes, leading to immune-mediated multi-organ failure. 2, 3
Clinical Presentation in Your Patient Context
Given the presentation of anemia, thrombocytopenia, elevated LDH, and significantly elevated ferritin, this patient demonstrates the classic laboratory signature of HLH:
Cytopenias affecting ≥2 cell lines (anemia and thrombocytopenia present here) result from bone marrow suppression by hypercytokinemia and hemophagocytosis. 1, 4
Markedly elevated ferritin (the "significantly elevated" ferritin mentioned) reflects both macrophage activation and hepatocyte damage from the inflammatory cascade; ferritin >10,000 ng/mL strongly suggests HLH, particularly when associated with organ toxicities. 5, 2
Elevated LDH indicates tissue damage from the ongoing inflammatory process and cellular destruction. 4
Additional cardinal features to assess include persistent high fever (often refractory to antimicrobials), hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, elevated transaminases, and neurological symptoms. 1, 4, 6
Diagnostic Approach
The HLH-2004 diagnostic criteria require either molecular diagnosis consistent with HLH OR at least 5 of these 8 criteria: 1
- Fever
- Splenomegaly
- Cytopenias (≥2 lineages)
- Hypertriglyceridemia and/or hypofibrinogenemia
- Hemophagocytosis in bone marrow, spleen, or lymph nodes
- Low or absent NK cell activity
- Ferritin ≥500 μg/L
- Elevated soluble CD25 (IL-2 receptor)
Critical diagnostic pitfall: HLH presents with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome, making diagnosis challenging. 2 Do not delay empirical treatment while waiting for all criteria to be met—the uncontrolled inflammatory cascade progresses rapidly, and early recognition prevents irreversible organ damage. 1, 2
Identifying the Underlying Trigger
Determining the HLH subtype is essential because treatment differs significantly: 7
Infection-triggered HLH: Viral infections (EBV, CMV most common), but also invasive fungi and bacteria in immunosuppressed patients. 1
Malignancy-associated HLH: T-cell/NK-cell lymphomas predominate (35% of cases), followed by B-cell lymphomas including DLBCL (32%), and Hodgkin lymphoma (6%). 5, 1 In male patients with lymphoma and EBV-driven HLH, test for X-linked lymphoproliferative syndrome (24% develop malignancy, usually Hodgkin lymphoma). 1
Macrophage Activation Syndrome (MAS): A specific HLH subtype occurring exclusively in patients with underlying autoimmune diseases (Still's disease, SLE, vasculitis). 7 Free IL-18 levels and S100A12 can differentiate MAS from other HLH forms. 7
HLH during chemotherapy: Develops from infections occurring due to chemotherapy-induced immunosuppression. 5, 1
Co-triggers are common—viral infections often act as co-triggers in malignancy-associated HLH, and it may be difficult to differentiate when both malignancy reactivation and infection coexist. 1
Management Principles
Treatment must simultaneously target both the hyperinflammation and the underlying trigger: 2
First-Line Treatment
- High-dose corticosteroids (dexamethasone or methylprednisolone 1g/day IV for 3-5 days) for most secondary HLH cases. 1, 7
- Treat the underlying cause concurrently: antimicrobials for infections, chemotherapy for malignancies, or disease-modifying therapy for autoimmune conditions. 1, 2
- Consider IVIG in severe cases. 1
Second-Line Options (if inadequate response to corticosteroids after 48-72 hours)
Refractory Cases
Monitor response every 12 hours: ferritin levels, cell counts, triglycerides, fibrinogen, and clinical status. 1 For CAR T-cell-related HLH specifically, manage as grade 3 cytokine-release syndrome with close monitoring; if no improvement after 48-72 hours, escalate to HLH-2004 protocol. 5
Prognosis and Critical Considerations
Mortality remains high, especially in adults with malignancy-associated HLH. 1, 3 Factors associated with higher mortality include shock at ICU admission, platelet count <30 g/L, and HLH associated with T-cell lymphomas. 1
Without treatment to suppress the overactive immune system, HLH leads to terminal multiple organ failure and death. 2 The pathophysiology explains why rapid deterioration occurs despite treating the underlying infection or malignancy—the hyperinflammatory cascade itself becomes the primary threat. 2
Age-related differences matter: Primary HLH is most common in children, while secondary HLH predominates in adults with different triggers, organ reserve, and clinical presentations. 2 Do not apply pediatric HLH protocols directly to adults without dose adjustments. 7