# Hemophagocytic Lymphohistiocytosis

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**Author:** Andrew Bland, MD, FACP, FAAP

## Executive Summary

**Key Points**

- HLH is a life-threatening hyperinflammatory syndrome driven by uncontrolled activation of cytotoxic T lymphocytes and macrophages, producing a self-amplifying cytokine storm dominated by IFN-γ (1,2)
- Two major diagnostic frameworks exist: the HLH-2004 criteria (≥5 of 8 criteria required) and the HScore (continuous probability score for reactive HLH in adults) (3,4)
- Primary (familial) HLH is caused by biallelic mutations in perforin/granzyme pathway genes (PRF1, UNC13D, STX11, STXBP2, RAB27A); secondary HLH is triggered by infection, malignancy, autoimmune disease, or immunosuppression (1)
- Soluble CD25 (sIL-2R) \>2,400 U/mL and ferritin \>10,000 ng/mL are the most diagnostically specific laboratory values, though neither is pathognomonic (3,5)
- First-line treatment is the HLH-94/2004 protocol (dexamethasone + etoposide ± cyclosporine); emapalumab (anti-IFN-γ) was FDA-approved in 2018 for primary or refractory HLH (~63% response) (6)
- Allogeneic HSCT is curative in primary HLH and in HLH secondary to refractory lymphoma (7)
- Renal involvement occurs in 30–60% of HLH cases and includes AKI from hemodynamic compromise, TMA, hemoglobinuria-associated tubular injury, and direct macrophage infiltration

## 1. Epidemiology and Classification

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.

### Secondary HLH Triggers

| 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 |

## 2. Pathophysiology

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).

**The Cytokine Storm Cascade:**

1.  Surviving macrophages continue presenting antigen, stimulating CTLs
2.  CTLs secrete massive amounts of IFN-γ
3.  IFN-γ activates macrophages to overproduce IL-6, IL-18, TNF-α, IL-12, IL-10
4.  Self-amplifying cycle drives: fever (IL-1/IL-6/TNF-α), cytopenias (macrophage-mediated hematopoietic cell destruction), hepatosplenomegaly (macrophage infiltration), coagulopathy (cytokine-driven fibrinolytic activation), CNS involvement (CNS macrophage infiltration), hemophagocytosis (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.

## 3. Clinical Presentation

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.

### Clinical Features by Frequency

| 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% |

**Diagnostic Mimics:** HLH is commonly confused with sepsis (fever, cytopenias, multiorgan dysfunction), lymphoma (lymphadenopathy, weight loss, hepatosplenomegaly), hemolytic uremic syndrome (MAHA, thrombocytopenia, AKI), and autoimmune disease — driving significant diagnostic delay.

## 4. Diagnostic Criteria

### 4.1 HLH-2004 Criteria

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 |

**Important Limitations:** These criteria were derived from pediatric primary HLH and have variable sensitivity/specificity in adult secondary HLH. Hemophagocytosis is present in only 40–70% early in illness (repeat biopsy improves yield). Ferritin ≥500 ng/mL is nonspecific; most clinicians use ≥10,000 ng/mL as the diagnostically meaningful threshold (sensitivity ~90%, specificity ~96% in pediatric series).

### 4.2 HScore

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) |

**HScore Interpretation:**

- **HScore ≥169:** Probability \>93% for HLH
- **HScore \<90:** HLH unlikely (\<1%)

The HScore is available as a free online calculator and has been validated in ICU, hematology, and rheumatology populations.

## 5. Diagnostic Workup

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.

### Confirmatory Workup

- CBC with differential (cytopenias)
- CMP, LFTs, LDH (hepatitis pattern, AKI)
- Coagulation panel: PT, aPTT, fibrinogen, D-dimer (DIC pattern)
- Ferritin (if \>10,000 ng/mL, highly specific; repeat q24–48h to track trajectory)
- Fasting triglycerides
- Soluble CD25 (sIL-2R): \>2,400 U/mL supports diagnosis; \>10,000 U/mL indicates severe disease
- Bone marrow aspirate and biopsy (hemophagocytosis, lymphoma infiltration)
- NK-cell function assay (send to reference laboratory)
- Genetic panel for primary HLH (PRF1, UNC13D, STX11, STXBP2, RAB27A, AP3B1, LYST) — especially in children and young adults

### Trigger Evaluation

- **Infectious:** EBV PCR and IgM/IgG, CMV PCR, HIV Ag/Ab, parvovirus B19, hepatitis serologies, blood and urine cultures, fungal serologies
- **Autoimmune:** ANA, anti-dsDNA, ferritin:ESR ratio (extremely elevated in MAS/Still’s), complement
- **Malignancy:** CT chest/abdomen/pelvis with contrast, PET-CT if lymphoma suspected, bone marrow biopsy pathology review
- Consider LP if CNS symptoms present (CSF pleocytosis in CNS HLH)

## 6. Treatment

### 6.1 HLH-94 and HLH-2004 Protocols

The HLH-94 protocol established the foundational treatment framework (1):

- **Dexamethasone** 10 mg/m²/day for 2 weeks, then tapering over 8 weeks
- **Etoposide** 150 mg/m² IV twice weekly for 2 weeks, then weekly for 6 weeks

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.

### 6.2 Emapalumab (Gamifant)

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 |

### 6.3 Other Emerging Approaches

| 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 |

### 6.4 Allogeneic HSCT

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.

## 7. Renal Complications

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 |

**Prognosis:** Renal involvement is associated with worse overall survival and longer ICU stay. AKI requiring RRT occurs in approximately 10–15% of hospitalized HLH cases. Renal outcomes parallel overall disease control; etoposide-based therapy and emapalumab have demonstrated improvement in AKI as a secondary endpoint.

## 8. Special Populations

### Neonatal HLH

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.

### Adult Secondary HLH

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).

### CAR-T–Associated IEC-HS

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.

### Checkpoint Inhibitor–Associated HLH

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.

## 9. Prognosis

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.

### Adverse Prognostic Factors

- CNS involvement at diagnosis
- Age \>30 years
- Hemoglobin \<7 g/dL
- Platelet count \<40,000/μL
- AST \>30x ULN
- Lymphoma as the trigger
- Renal involvement
- Failure to achieve response within 2 weeks of etoposide initiation (7)

## References

1.  Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. *Pediatr Blood Cancer*. 2007;48(2):124-131. [PubMed](https://pubmed.ncbi.nlm.nih.gov/16937360/)
2.  Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. *Annu Rev Med*. 2012;63:233-246. [PubMed](https://pubmed.ncbi.nlm.nih.gov/22248322/)
3.  Henter JI, Samuelsson-Horne A, Aricò M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. *Blood*. 2002;100(7):2367-2373. [PubMed](https://pubmed.ncbi.nlm.nih.gov/12239144/)
4.  Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. *Arthritis Rheumatol*. 2014;66(9):2613-2620. [PubMed](https://pubmed.ncbi.nlm.nih.gov/24782338/)
5.  Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult patient. *Blood*. 2015;125(19):2908-2914. [PubMed](https://pubmed.ncbi.nlm.nih.gov/25758828/)
6.  Jordan MB, Allen CE, Greenberg J, et al. Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: Recommendations from the North American Consortium for Histiocytosis (NACHO). *Pediatr Blood Cancer* 2019. [PubMed 31339233](https://pubmed.ncbi.nlm.nih.gov/31339233/).
7.  Bergsten E, Horne A, Aricó M, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. *Blood*. 2017;130(25):2728-2738. [PubMed](https://pubmed.ncbi.nlm.nih.gov/28935695/)
8.  La Rosée P, Horne AC, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. *Blood*. 2019;133(23):2465-2477. [PubMed](https://pubmed.ncbi.nlm.nih.gov/30992265/)
9.  Locatelli F, Jordan MB, Allen C, et al. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. *N Engl J Med*. 2020;382(19):1811-1822. [PubMed](https://pubmed.ncbi.nlm.nih.gov/32374962/)
10. Lehmberg K, Sprekels B, Nichols KE, et al. Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents. *Br J Haematol*. 2015;170(4):539-549. [PubMed](https://pubmed.ncbi.nlm.nih.gov/25940575/)
11. Schulert GS, Grom AA. Pathogenesis of macrophage activation syndrome and potential for cytokine-directed therapies. *Annu Rev Med*. 2015;66:145-159. [PubMed](https://pubmed.ncbi.nlm.nih.gov/25386930/)
12. Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. *Lancet*. 2014;383(9927):1503-1516. [PubMed](https://pubmed.ncbi.nlm.nih.gov/24290661/)

Andrew Bland, MD, FACP, FAAP \| Clinical Mastery Series \| Urine Nephrology Now

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