A can’t-miss emergency
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome in which uncontrolled activation of macrophages and cytotoxic T cells produces a cytokine storm, multi-organ injury, and rapid death if untreated. Mortality without therapy approaches 100%, and survival is time-dependent — recognise it early and escalate immediately. It is frequently mistaken for sepsis or refractory fever; the clinician who keeps HLH on the differential in a sick child with persistent fever and cytopenias saves lives.
Definition and epidemiology
HLH is divided into primary (familial) forms — autosomal-recessive defects in cytotoxic granule pathways (PRF1, UNC13D, STX11, STXBP2), typically presenting in infancy — and secondary (acquired) HLH triggered by infection (EBV is the classic and common trigger, also dengue, leishmaniasis, tuberculosis — all highly relevant in India), malignancy (especially lymphoma), or rheumatologic disease. When HLH complicates an autoimmune condition (notably systemic JIA or SLE) it is termed macrophage activation syndrome (MAS). Any age can be affected; familial disease clusters in the first year of life.
Clinical features
The cardinal picture is prolonged high fever unresponsive to antibiotics, hepatosplenomegaly, and progressive cytopenias. Look for jaundice and deranged liver function, coagulopathy with hypofibrinogenaemia and bleeding, CNS involvement (irritability, seizures, altered sensorium), oedema, and a strikingly elevated ferritin. The combination of falling counts, falling fibrinogen, and rising ferritin/triglycerides in a febrile child is the hallmark trajectory.
Diagnosis
The HLH-2004 criteria support diagnosis when a molecular diagnosis consistent with HLH is present, OR 5 of 8 clinical/laboratory criteria are met: (1) fever; (2) splenomegaly; (3) cytopenias affecting ≥2 lineages (Hb <90 g/L, platelets <100 ×10⁹/L, neutrophils <1.0 ×10⁹/L); (4) hypertriglyceridaemia (fasting ≥3.0 mmol/L / ≥265 mg/dL) and/or hypofibrinogenaemia (≤1.5 g/L); (5) haemophagocytosis in marrow, spleen, or lymph node; (6) low or absent NK-cell activity; (7) ferritin ≥500 µg/L (markedly higher values are more specific); (8) elevated soluble IL-2 receptor (sCD25). Absence of marrow haemophagocytosis does not exclude HLH. The H-score offers a probability-based alternative (a cutoff around 168–169 performs well in older patients). Do not wait for every test — start workup and treatment in parallel and pursue the underlying trigger.
See the full criteria: Hemophagocytic Lymphohistiocytosis
Red flags
- Ferritin in the thousands to tens of thousands with falling counts and fibrinogen — treat as HLH until disproven.
- Persistent fever attributed to “sepsis” that does not respond to broad-spectrum antibiotics.
- New neurological signs or CSF pleocytosis — CNS-HLH, a poor-prognosis subset.
- Rapidly worsening coagulopathy and transaminitis — impending multi-organ failure.
- Known sJIA/SLE with sudden cytopenias and paradoxically falling ESR — suspect MAS.
Management overview
HLH is a haematology/intensive-care emergency — involve them at the first suspicion. Stabilise organ dysfunction and coagulopathy while urgently identifying and treating the trigger; treating the trigger alone may suffice in milder secondary HLH. For severe or progressive disease, the HLH-94/HLH-2004 protocol (dexamethasone plus etoposide, with intrathecal therapy for CNS disease) is standard; emapalumab (anti-IFN-γ) is an option in refractory/primary disease. MAS is typically managed with high-dose corticosteroids, anakinra, and ciclosporin. Primary/familial HLH and refractory secondary HLH require allogeneic haematopoietic stem cell transplantation for cure. Test EBV viral load and screen for endemic infections (dengue, leishmaniasis, TB) before assuming a non-infectious cause.
References
- Henter JI, et al. HLH-2004 guidelines. Pediatr Blood Cancer. 2007;48(2):124-131.
- Fardet L, et al. The HScore. Arthritis Rheumatol. 2014;66(9):2613-2620.
- La Rosée P, et al. Management of HLH. Blood. 2019;133(23):2465-2477.
- Nelson Textbook of Pediatrics, 21st ed.
Decision support for qualified clinicians only — verify against current primary guidelines and your clinical judgement.