ImmunologyTier 1Medical Sciences concept

Haemophagocytic lymphohistiocytosis (HLH) - pathophysiology

Core concept

Failure of the perforin-granzyme cytotoxic killing pathway -> the immune response cannot be terminated

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NK / CD8 cytotoxicity defective

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Form	Cause
Primary (familial), AR	PRF1 (perforin), UNC13D/Munc13-4, STX11, STXBP2 - degranulation machinery
Syndromic	Chediak-Higashi (LYST), Griscelli type 2 (RAB27A), Hermansky-Pudlak type 2, XLP1 (SH2D1A) - fulminant EBV-HLH, XLP2 (XIAP)
Secondary	Infection (EBV the commonest; CMV, HIV, leishmania, TB, dengue), malignancy (T/NK lymphoma), autoimmune -> macrophage activation syndrome (systemic JIA, adult-onset Still's, SLE), CAR-T and checkpoint inhibitors

Clinical

Unremitting high fever, hepatosplenomegaly, lymphadenopathy, encephalopathy/seizures, rash, jaundice
A "septic" patient who does not improve on antibiotics and has a ferritin in the thousands

Laboratory - the pattern is the diagnosis

Cytopenias >=2 lineages (Hb <90, platelets <100, neutrophils <1.0)
Ferritin markedly raised - >500 microg/L is the criterion, but >10,000 microg/L is ~90% specific in children
Fibrinogen LOW (<1.5 g/L) and triglycerides HIGH (>3.0 mmol/L) - macrophage plasminogen activator and lipoprotein lipase inhibition
Soluble CD25 (sIL-2R) raised; NK cell function low or absent
Transaminitis, high LDH, high bilirubin, hyponatraemia, high D-dimer
The paradoxical falling ESR - ESR depends on fibrinogen; consumptive hypofibrinogenaemia drops the ESR while CRP and ferritin climb. A falling ESR with a rising CRP is the discriminating clue.
Haemophagocytosis on marrow is neither sensitive nor specific and is not required

Criteria

HLH-2004: 5 of 8 - fever, splenomegaly, cytopenias >=2 lines, hypertriglyceridaemia and/or hypofibrinogenaemia, haemophagocytosis, low/absent NK activity, ferritin >=500, sCD25 raised
HScore for adults (probability-based, uses immunosuppression, organomegaly, cytopenias, ferritin, triglycerides, fibrinogen, AST, haemophagocytosis)
MAS in systemic JIA uses different thresholds - ferritin >684 with 2 of (platelets <=181, AST >48, triglycerides >1.76 g/L, fibrinogen <=3.6 g/L); "normal" counts can be a falling trend from a high inflammatory baseline

Time-critical - untreated HLH is fatal in weeks. Do not wait for all 5 criteria
Search relentlessly for the trigger while treating - EBV PCR, HIV, CMV, blood film, CT, bone marrow, lymph node biopsy, autoimmune serology
Treatment
- HLH-94/2004: dexamethasone + etoposide (+/- ciclosporin), intrathecal methotrexate if CNS involvement
- EBV-HLH -> add rituximab (removes the B-cell reservoir)
- MAS -> high-dose corticosteroid first-line, then anakinra (IL-1); etoposide is usually not needed
- Emapalumab (anti-IFN-gamma) for primary/refractory HLH
- Familial disease requires allogeneic HSCT for cure
Recognise CAR-T-associated HLH/macrophage activation - overlaps with CRS; tocilizumab, steroid, anakinra

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