Diagnosis, Evaluation, and Management — A Comprehensive Clinical Review
Author: Andrew Bland, MD, MBA, MS
HLH has an estimated incidence of 1.2 per million persons per year in population-based studies, though this is widely regarded as an underestimate given frequent misdiagnosis (1). No significant sex predilection. Primary HLH presents predominantly in early childhood (>70% before age 2) but can manifest in adulthood.
| Category | Key Triggers | Details |
|---|---|---|
| Infectious | EBV (most common), CMV, HHV-8, parvovirus B19, HIV, disseminated fungi, Leishmaniasis | EBV accounts for ~30–40% of infection-associated cases |
| Malignancy-associated | T-cell and NK-cell lymphomas | HLH occurs in 20–30% of NK/T-cell lymphoma; may be presenting manifestation of occult lymphoma |
| Autoimmune (MAS) | sJIA, adult-onset Still's disease, SLE | MAS is the HLH-equivalent in rheumatologic disease |
| Iatrogenic | ICI therapy, CAR-T cell therapy (IEC-HS), allogeneic HSCT | Increasingly recognized in oncologic practice |
The central defect in primary HLH is impaired cytotoxic T lymphocyte (CTL) and NK-cell degranulation. Under normal circumstances, CTLs eliminate activated macrophages by delivering perforin and granzyme B through lytic granule fusion at the immunologic synapse. When this pathway fails — as with PRF1 mutations (perforin deficiency), UNC13D mutations (impaired granule priming), or STX11/STXBP2 mutations (impaired membrane fusion) — macrophages are not killed efficiently (1,2).
In secondary HLH, an overwhelming inflammatory trigger exposes a relative deficiency in cytotoxic clearance capacity, producing the same downstream cytokine amplification loop even without identifiable biallelic germline mutations.
The classic presentation is a febrile illness that fails to respond to empiric antibiotics, with progressive cytopenias, organomegaly, and laboratory evidence of hyperinflammation. The trajectory is typically days to 2–3 weeks from symptom onset to diagnosis if recognized promptly, but delays of weeks to months are common.
| Feature | Approximate Frequency |
|---|---|
| Fever (>38.5°C, persistent or episodic) | >95% |
| Splenomegaly | 85–90% |
| Cytopenias (≥2 cell lines) | 85–95% |
| Hyperferritinemia | >90% |
| Elevated sCD25 (sIL-2R) | >90% |
| Elevated triglycerides | 70–80% |
| Fibrinogen <150 mg/dL or elevated D-dimer | 70–80% |
| Hepatitis / elevated LFTs | 70–80% |
| Hemophagocytosis on bone marrow aspirate | 40–70% |
| CNS involvement (irritability, seizures, meningismus) | 30–50% |
| AKI | 30–60% |
| Rash | 15–35% |
Require ≥5 of the following 8 findings for diagnosis (3):
| # | Criterion | Threshold |
|---|---|---|
| 1 | Fever | ≥38.5°C |
| 2 | Splenomegaly | Clinical or imaging |
| 3 | Cytopenias (≥2 cell lines) | Hgb <9 g/dL, Plt <100K, ANC <1,000 |
| 4 | Hypertriglyceridemia or hypofibrinogenemia | Fasting TG ≥265 mg/dL or fibrinogen ≤150 mg/dL |
| 5 | Hemophagocytosis | On BM, spleen, or lymph node biopsy |
| 6 | Low or absent NK-cell cytotoxicity | Reference lab assay |
| 7 | Ferritin | ≥500 ng/mL |
| 8 | sCD25 (soluble IL-2 receptor) | ≥2,400 U/mL |
Developed by Fardet et al. (4), validated for adult secondary/reactive HLH. A continuous probability score with 9 parameters:
| Parameter | Points |
|---|---|
| Immunosuppressed (HIV, chronic steroid, azathioprine) | 0 (no), +18 (yes) |
| Temperature (°C) | 0 (<38.4), +33 (38.4–39.4), +49 (>39.4) |
| Organomegaly | 0 (none), +23 (hepato- or splenomegaly), +38 (both) |
| Number of cytopenias | 0 (1), +24 (2), +34 (3) |
| Ferritin (ng/mL) | 0 (<2000), +35 (2000–6000), +50 (>6000) |
| Triglycerides (mmol/L) | 0 (<1.5), +44 (1.5–4), +64 (>4) |
| Fibrinogen (g/L) | 0 (>2.5), +30 (≤2.5) |
| SGOT (U/L) | 0 (<30), +19 (≥30) |
| Hemophagocytosis on BM aspirate | 0 (no), +35 (yes) |
The HScore is available as a free online calculator and has been validated in ICU, hematology, and rheumatology populations.
A systematic workup pursues two parallel goals: confirming the HLH diagnosis and identifying the underlying trigger. Both must be pursued simultaneously because trigger-directed therapy significantly improves outcomes.
The HLH-94 protocol established the foundational treatment framework (1):
The HLH-2004 protocol added cyclosporine A (target trough 200 μg/L) from initiation for CNS protection and relapse reduction; however, the addition did not significantly improve 5-year overall survival compared with HLH-94 in prospective comparison (7).
Overall survival at 5 years for primary HLH treated with HLH-94/2004 followed by HSCT is approximately 54–60% (7). Survival is substantially worse with delayed diagnosis and in adults with T/NK-cell lymphoma-driven HLH.
A fully human anti-IFN-γ monoclonal antibody, FDA-approved November 2018 for primary HLH in patients with refractory, recurrent, or progressive disease (6). By neutralizing IFN-γ, emapalumab interrupts the central cytokine amplification loop without the myelosuppressive toxicity of etoposide.
| Parameter | Details |
|---|---|
| Mechanism | Neutralizes IFN-γ — central driver of HLH cytokine storm |
| Response rate | 63% in refractory/relapsed primary HLH |
| Dosing | 1 mg/kg IV twice weekly; escalate to 3 or 6 mg/kg based on response |
| Bridge to HSCT | All responding patients were able to proceed to HSCT |
| Key safety signal | Serious infection from IFN-γ neutralization |
| Mandatory prophylaxis | Antibacterial, antifungal, and anti-pneumocystis agents |
| Agent | Mechanism | Evidence |
|---|---|---|
| Ruxolitinib (JAK1/2 inhibitor) | Inhibits JAK-STAT signaling downstream of IFN-γ and IL-6 | Compelling case series for secondary HLH/MAS, especially ICI-associated HLH and Still’s disease-MAS; not FDA-approved for HLH |
| Anakinra (IL-1Ra) | IL-1 receptor antagonist | Demonstrated efficacy in sJIA-MAS; less evidence in primary or EBV-driven HLH |
| Tocilizumab (anti-IL-6) | IL-6 blockade | Utility contested; addresses one cytokine but not the dominant IFN-γ axis |
The only curative therapy for primary HLH and for HLH secondary to refractory malignancy (7). Reduced-intensity conditioning (RIC) regimens have improved transplant-related mortality. Five-year post-HSCT survival in favorable-risk primary HLH now approaches 60–70% at experienced centers.
Renal involvement in HLH is common (30–60% of cases) and mechanistically heterogeneous:
| Mechanism | Pathology | Clinical Features |
|---|---|---|
| Hemodynamic AKI | Prerenal physiology from cytokine-driven vasodilation and hepatic dysfunction | Responds to resuscitation and disease control |
| Macrophage infiltration | Direct infiltration of renal interstitium; AIN-like pattern with occasional granulomatous features | AKI with bland sediment |
| TMA | Cytokine-driven endothelial injury; MAHA, thrombocytopenia | Closely mimics TTP/HUS; must recognize as HLH-related |
| Hemoglobinuria-mediated tubular injury | Hemolysis deposits hemoglobin in tubular lumen; cast nephropathy | Analogous to myoglobinuric AKI |
Neonatal onset (first 4 weeks) is characteristically associated with biallelic PRF1 mutations. Liver failure, profound cytopenias, and CNS involvement predominate. Outcomes are poor without rapid HSCT.
Significantly worse prognosis than pediatric primary HLH, with 30-day mortality of 30–50% in ICU populations. EBV-associated lymphoma-driven HLH carries the worst prognosis (median survival <2 months without aggressive lymphoma-directed therapy). The HScore was specifically validated for this context (4).
Immune effector cell–associated HLH-like syndrome following CAR-T cell therapy shares the IFN-γ–driven pathophysiology. Managed with ruxolitinib, anakinra, and/or emapalumab in addition to corticosteroids. Must be distinguished from cytokine release syndrome (CRS), which is IL-6–mediated and responds to tocilizumab.
PD-1/PD-L1 and CTLA-4 inhibitor therapy can trigger HLH through dysregulated T-cell activation. Corticosteroids are first-line; ruxolitinib has emerging data. Rechallenge with checkpoint inhibitors is generally contraindicated.
Without treatment, HLH carries mortality approaching 100%. With HLH-94/2004-based therapy, 3-year overall survival was 61% for primary HLH treated with HSCT in the largest modern pediatric registry.
Andrew Bland, MD, MBA, MS | Clinical Mastery Series | Urine Nephrology Now
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