HaematologyTier 1Disease (DEADMAN)

Haemophagocytic lymphohistiocytosis

Description

Hyperinflammatory syndrome, not a malignancy - uncontrolled macrophage and T-cell activation with a cytokine storm
- Failure of the normal off switch: NK cells and CD8 T cells cannot kill the activated antigen-presenting cell -> persistent stimulation -> cytokine flood -> tissue damage
*Always ask "what triggered it?" - the trigger and the HLH need treating simultaneously*

Two forms

Primary (familial) - biallelic defect of granule-mediated cytotoxicity. Infants/children, but adult-onset presentations occur with hypomorphic variants
Secondary (acquired) - infection, malignancy, autoimmune, drug, immunotherapy
- Macrophage activation syndrome (MAS) = the rheumatological form (sJIA, adult-onset Still, SLE)

Clinical picture: unexplained persistent fever + cytopenias + hepatosplenomegaly + very high ferritin in a deteriorating patient
- Mimics sepsis and is repeatedly missed as "culture-negative sepsis not responding to antibiotics"

Epidemiology

Familial HLH ~1 in 50,000 live births; median age of presentation <1 year (~70-80% present before age 1)
Secondary HLH: any age, increasingly recognised in adults; true incidence unknown, substantially under-diagnosed
Adult HLH: malignancy-associated is the largest group (~30-50%), then infection
EBV is the commonest infectious trigger worldwide; higher incidence of EBV-HLH in East Asian populations

Aetiopathogenesis

Mechanism

Defective perforin/granzyme-mediated cytotoxicity
- -> cannot lyse the infected/activated APC
- -> prolonged CD8 T cell - APC synapse
- -> IFN-gamma, IL-1beta, IL-6, IL-18, TNF, sIL-2R (CD25) flood
- -> macrophage activation, haemophagocytosis, endothelial injury, multi-organ failure
Downstream consequences that become the diagnostic criteria:
- Macrophage ferritin release -> extreme hyperferritinaemia
- TNF -> dec lipoprotein lipase -> hypertriglyceridaemia
- Macrophage plasminogen activator -> hypofibrinogenaemia
- Cytokine-driven marrow suppression + consumption -> cytopenias

Primary - genes

Gene	Protein / syndrome
PRF1	Perforin (FHL2)
UNC13D	Munc13-4 (FHL3)
STX11, STXBP2	Syntaxin-11, Munc18-2 (FHL4, FHL5)
SH2D1A / XIAP	X-linked lymphoproliferative disease - EBV-triggered
LYST	Chediak-Higashi
RAB27A	Griscelli type 2

Secondary - triggers

Infection - EBV (commonest), CMV, HIV, HSV, influenza, SARS-CoV-2, leishmania, TB, histoplasma, dengue
Malignancy - T-cell and NK-cell lymphoma especially, Hodgkin, DLBCL, leukaemia
Rheumatological (MAS) - sJIA, adult-onset Still disease, SLE
Immunodeficiency - primary, post-transplant
Drugs - DRESS; and iatrogenic immune activation: CAR-T, immune checkpoint inhibitors, bispecific antibodies
Metabolic - lysinuric protein intolerance, propionic acidaemia

Diagnosis

HLH-2004 criteria - 5 of 8

1. Fever >38.5 C

2. Splenomegaly

3. Cytopenias in >=2 lineages - Hb <90, platelets <100, neutrophils <1.0

4. Hypertriglyceridaemia (fasting >3.0 mmol/L) and/or hypofibrinogenaemia (<1.5 g/L)

5. Haemophagocytosis in marrow, spleen, node or liver

6. Low or absent NK cell activity

7. Ferritin >=500 microg/L

8. Soluble CD25 (sIL-2R) elevated (>2 SD above age-adjusted norm)

Or a molecular diagnosis consistent with HLH (which alone is sufficient)
*Practical points that matter more than the list itself:*
- Ferritin >=500 is far too permissive in adults. >5,000 is much more specific; >10,000 with fever and cytopenias should be treated as HLH until disproven
- Haemophagocytosis is neither sensitive nor specific - absent early in up to a third, and seen in sepsis and post-transfusion. Its absence never excludes HLH
- sCD25 and NK function are send-away tests - do not wait for them to start treatment

HScore

Weighted score for secondary HLH in adults - temperature, organomegaly, cytopenias, triglycerides, fibrinogen, ferritin, AST, haemophagocytosis, known immunosuppression
Cut-off ~169 - ~90% sensitivity, ~86% specificity

Supporting features

Very high LDH, transaminitis, hyperbilirubinaemia, coagulopathy, hyponatraemia, high D-dimer
Low/absent fibrinogen with a high ferritin is close to pathognomonic in the right setting
CNS: seizures, encephalopathy, cranial nerve palsies; CSF pleocytosis/high protein in ~50% with CNS disease - do LP and MRI brain

Establish the trigger in parallel

EBV, CMV, HIV, adenovirus PCR, blood cultures, leishmania serology/PCR where relevant
CT chest/abdo/pelvis +/- PET, marrow aspirate/trephine, node biopsy - actively hunt lymphoma
ANA, rheumatoid factor, complement; ferritin >>, glycosylated ferritin <20% in adult-onset Still
Genetic panel (PRF1, UNC13D, STX11, STXBP2, XIAP) in all children, and in adults with relapse, family history or no trigger

Management

Time-critical. Untreated fulminant HLH kills within weeks. Two decisions: how sick, and what triggered it.

A. Stable patient with an identified, treatable trigger

Treat the trigger and support - may be sufficient without HLH-directed chemotherapy
- Antimicrobials, ART, stop the culprit drug (DRESS)
- Lymphoma-associated HLH: the lymphoma treatment is the HLH treatment - do not delay chemotherapy waiting for HLH to settle
Corticosteroid +/- IVIG while the trigger is being treated

B. Acutely unwell, deteriorating, or no identified trigger

HLH-94/HLH-2004 backbone
- Dexamethasone (tapering over 8 weeks) + etoposide
- Ciclosporin in continuation
- Etoposide is disproportionately effective - it selectively deletes activated T cells. Dose-reduce, do not omit, in renal/hepatic impairment
CNS disease -> add intrathecal methotrexate + hydrocortisone
EBV-driven -> add rituximab (depletes the B-cell EBV reservoir)
MAS -> high-dose corticosteroid + anakinra (IL-1 blockade), ciclosporin; etoposide reserved for refractory MAS

C. Refractory disease - targeted cytokine blockade

Emapalumab - anti-IFN-gamma monoclonal; licensed for primary HLH refractory/intolerant to conventional therapy, increasingly used in secondary HLH and MAS
Ruxolitinib - JAK1/2 inhibitor, blocks signalling downstream of multiple HLH cytokines
Alemtuzumab, ATG as salvage

D. Definitive therapy

Allogeneic HSCT is the only cure for primary HLH - and for relapsing/refractory secondary HLH
- Reduced-intensity conditioning preferred; proceed once disease is controlled, do not wait for a perfect remission

E. Supportive

ICU-level support; aggressive product support - fibrinogen/cryoprecipitate, platelets
Broad antimicrobial cover; PJP and antifungal prophylaxis with prolonged etoposide/steroid
Avoid attributing deterioration to sepsis alone - it delays HLH treatment and that is the commonest fatal error

Associations

EBV and X-linked lymphoproliferative disease
T-cell and NK-cell lymphoma (subcutaneous panniculitis-like, hepatosplenic, extranodal NK/T nasal type)
Systemic JIA and adult-onset Still disease (MAS)
SLE, dermatomyositis, Kawasaki disease
DRESS
CAR-T cell therapy and immune checkpoint inhibitors - overlaps with CRS/IEC-HS
Chediak-Higashi, Griscelli type 2, Hermansky-Pudlak type 2 (all with partial albinism)
Post-transplant, HIV, visceral leishmaniasis
Pregnancy

Natural history & complications

Untreated primary HLH: median survival <2-3 months
With HLH-94 + allogeneic HSCT: 5-yr survival ~50-70% in primary disease
Adult secondary HLH mortality ~40-60%; malignancy-associated is the worst subgroup

Adverse markers

Malignancy as the trigger, age >50, very high ferritin and failure of ferritin to fall with treatment
Hypoalbuminaemia, coagulopathy, high bilirubin, CNS involvement, need for ICU
Delay to diagnosis

Monitoring

Falling ferritin is the best available response marker - track it every few days
Fibrinogen, triglycerides, sCD25, cytopenias, LFTs
Relapse is common - a second febrile cytopenic episode is HLH again until proven otherwise

Complications

Multi-organ failure, DIC and major haemorrhage, ARDS
CNS: seizures, encephalopathy, long-term neurocognitive sequelae
Opportunistic infection from treatment
Etoposide-related secondary MDS/AML; transplant-related morbidity

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