Hemophagocytic lymphohistiocytosis (HLH)

Pathophysiology

• Mechanism: failure of cytotoxic T cells / NK cells to kill target cells → unopposed, uncontrolled T-cell and macrophage activation → cytokine storm (IFN-γ, IL-1, IL-6, IL-12, IL-18, sCD25/sIL-2R, TNF) → multiorgan dysfunction and hemophagocytosis.
• Cellular event: proliferation and activation of benign macrophages with phagocytosis of hematopoietic elements throughout the reticuloendothelial (RE) system. Familial HLH has identified defects in cytotoxic T-cell / NK-cell granule pathways; the mechanism of acquired (reactive) forms is not fully understood.
• Primary (familial) HLH: mutations in the cytolytic granule pathway, PRF1 (perforin), UNC13D (Munc13-4), STX11, STXBP2 (Munc18-2), RAB27A; X-linked (SH2D1A/SAP in XLP1, classically EBV-triggered; XIAP/BIRC4 in XLP2, HLH often recurrent and EBV-independent).
• Secondary (reactive) HLH:
  • Infection: EBV (#1 viral trigger), CMV, HHV-8, HSV, HIV, parvovirus B19, adenovirus, hepatitis virus, leishmania, malaria, TB, rickettsial, spirochete, fungi.
  • Malignancy: lymphoma (T/NK > B-cell), AML, MDS, myeloma, T-cell leukemias, hepatosplenic T-cell, metastatic carcinoma/melanoma.
  • Autoimmune (MAS, macrophage activation syndrome): systemic JIA, SLE, adult-onset Still, Kawasaki.
  • Drugs: IO (checkpoint inhibitors), DRESS syndrome, dasatinib.
  • CAR-T cytokine release: CRS-associated HLH-like.
  • Post-transplant: allogeneic HSCT.

Diagnostic criteria (HLH-2004)

• Diagnosis: a molecular diagnosis consistent with HLH (e.g., pathologic mutation of PRF1, UNC13D/Munc13-4, STXBP2/Munc18-2, RAB27A, STX11, SH2D1A, or BIRC4) OR ≥5 of 8 clinical/laboratory criteria.

• Supporting findings (not required): hyponatremia, liver dysfunction, CSF pleocytosis, increased CSF protein, family history of possible or confirmed HLH.
• HScore: alternative scoring system, often used in adults.
• MAS criteria for systemic JIA: different, based on ferritin >684 plus other features.

Biomarkers: sIL-2R (sCD25) and ferritin

• sIL-2R (IL-2Rα, sCD25): widely expressed on T cells, B cells, monocytes, eosinophils, NK cells; cleaved from the cell surface by macrophage MMP9. It is a marker of immune activation across many inflammatory, autoimmune, infectious, lymphomatous, cirrhotic, and CKD states (sensitive but not specific).
• sIL-2R >5000 and a high sIL-2R / ferritin ratio have ~95% PPV for lymphoma-associated HLH.
• Ferritin >10,000 is highly predictive of HLH in pediatric cases; in adults it is nonspecific (also seen in liver failure, sepsis, hematologic malignancy, and iron overload).

Primary (familial) HLH

• Onset: ~70% diagnosed by age 1.
• Genetics: FHL-2 (most common) from PRF1 (perforin) mutations; perforin is a pore-forming granule protein that delivers granzymes into target cells (deficiency impairs killing with preserved degranulation). Granule exocytosis defects are UNC13D, STX11, STXBP2. FHL-3, FHL-4, FHL-5 from UNC13D (Munc13-4), STX11 (syntaxin 11), and STXBP2 (syntaxin-binding protein 2). FHL-1 maps to 9q21.3 to q22 (gene unknown). Can also be secondary to immunodeficiency syndromes: Chediak-Higashi, Griscelli, X-linked lymphoproliferative syndrome.
• Prognosis: familial HLH is lethal without allogeneic HSCT.

Adult / secondary HLH

• Most common cause in adults is malignancy (~50% of cases, most often lymphoma; also AML, MDS, myeloma, metastatic carcinoma/melanoma). Cancer-associated HLH carries the worst prognosis.
• Viral: herpesviruses (EBV, CMV, HHV-8, HSV), HIV, parvovirus, adenovirus, hepatitis virus.
• Bacterial/other: rickettsial, fungal, and spirochete-associated infections.

Workup

• Initial labs: CBC, retic, LDH, fibrinogen, triglycerides, ferritin, CMP, LFTs, coagulation panel, CK, sIL-2R (sCD25).
• Identify trigger: viral panel (EBV PCR, CMV, HSV, HIV), blood cultures, parasitology if travel, autoimmune panel, age-appropriate cancer evaluation (LDH, peripheral flow, BM biopsy, CT chest/abd/pelvis or PET-CT for lymphoma).
• Bone marrow biopsy: hemophagocytosis (sensitivity ~75%); identifies underlying lymphoma / leukemia.
• Genetic testing: for primary HLH (especially children, recurrent disease, family history).
• CNS involvement in ~30%: lumbar puncture if neurologic features (HLH cells in CSF, ↑ protein).

Treatment

• HLH-94 protocol (backbone): 8 weeks of etoposide + dexamethasone, followed by a continuation phase for familial, relapsing, or severe/persistent disease consisting of cyclosporine A with pulses of etoposide and dexamethasone until an acceptable donor is identified for HSCT. HLH-94 3-year OS ~55% (familial disease ~51%); 5-year OS ~54%.
• Familial HLH: HLH-94 induction → allogeneic HSCT with reduced-intensity conditioning. An alternative naive-patient regimen of anti-thymocyte globulin, prednisone, maintenance cyclosporine, and intrathecal methotrexate/corticosteroids reported ~82% short-term complete response.
• Adult HLH: high-dose steroids and etoposide. Allo-HSCT for genetic HLH and relapsed/refractory or persistent secondary HLH (and CNS-HLH). EBV association or initial severity alone is not an indication; successfully treated EBV-HLH does not routinely require transplant.
• Trigger-specific therapy:
  • EBV-HLH: IVIG, steroids, etoposide, +/- rituximab (rituximab targets CD20+ B cells, the reservoir in ordinary EBV infection, but EBV-HLH often infects T/NK cells where rituximab is ineffective, so it supplements, not replaces, etoposide/steroids).
  • MAS: high-dose glucocorticoids (backbone) plus anakinra (anti-IL-1, often early, rapid onset) and/or cyclosporine; IFN-γ blockade or etoposide for refractory disease. MTX and anti-TNF target the underlying rheumatic disease, not acute MAS.
  • Malignancy-associated: urgent cancer-directed therapy.
• Relapsed/refractory adult HLH: DEP regimen (doxorubicin/etoposide/methylprednisolone; CR ~27%, PR ~49%) or alemtuzumab (anti-CD52; ~75% bridged to SCT, long-term OS ~60%).
• Emapalumab (Gamifant): anti-IFN-γ mAb; R/R primary HLH ORR ~63%. FDA Nov 2018 for primary HLH; FDA Jun 2025 for HLH/MAS in adult and pediatric Still disease with inadequate response or intolerance to glucocorticoids, or recurrent MAS (NI-0501-06 and EMERALD trials).
• Ruxolitinib / JAK inhibitors: increasingly used and under study for refractory adult HLH.

CNS prophylaxis

• Children with progressive neurologic symptoms during therapy, or CSF abnormalities not improving after ~2 wks of systemic treatment, receive intrathecal methotrexate (HLH-94; HLH-2004 added intrathecal corticosteroid); it is not given routinely to all children.
• Adults have less CNS disease; consider CNS-directed/IT therapy for CNS involvement persisting or progressing despite systemic treatment (including persistent CSF abnormalities), not only overt neurologic signs.

HSCT

• Recommended for all patients with primary (genetic) HLH, and for adults with relapsed, refractory, or persistent secondary HLH or CNS-HLH; EBV association or initial severity alone is not an indication.
• Achieve the best feasible disease control before HSCT (response status affects outcomes), but CR is not mandatory and refractory disease may still proceed; main risks are transplant-related mortality and graft failure. Reduced-intensity conditioning yields better results, as does pre-transplant alemtuzumab.

Prognosis

• Primary HLH without HSCT: nearly fatal. With HSCT: 5-yr OS ~60 to 70%.
• Secondary HLH depends on trigger. Lymphoma-associated: poor without effective lymphoma-directed therapy. EBV-associated: variable. MAS: better outcomes with anakinra.

High yield (HLH)

• Ferritin >10,000: ~90% sensitive and ~96% specific for HLH in children; much less specific in adults (see Biomarkers).
• Treat the trigger: lymphoma-associated needs lymphoma-directed therapy urgently.
• EBV is the most common infectious trigger of secondary HLH; etoposide + dexamethasone (HLH-94) backbone, +/- rituximab and IVIG; allo-HSCT only if refractory, relapsed, or genetic.
• MAS (in JIA/SLE): anakinra (anti-IL-1) often first-line; rapid onset.
• Soluble CD25 / sIL-2R is highly sensitive for HLH but less specific; sIL-2R >5000 with a high sIL-2R/ferritin ratio suggests lymphoma-associated HLH.
• Emapalumab (Gamifant): anti-IFN-γ mAb; FDA Nov 2018 for primary HLH; FDA Jun 2025 for HLH/MAS in adult and pediatric Still disease (NI-0501-06 and EMERALD trials).
• Ruxolitinib increasingly used for refractory adult HLH.
• Hemophagocytosis on BM: supportive but not required (sensitivity ~75%).
• CAR-T can cause IEC-HS, an HLH-like syndrome distinct from CRS (often emerges as CRS resolves); treat with anakinra +/- steroids. Tocilizumab is for concurrent CRS, not isolated IEC-HS.