ICU · haematology-coagulation
Hemophagocytic Lymphohistiocytosis (HLH) and Macrophage Activation Syndrome (MAS) in the ICU
Also known as Hemophagocytic lymphohistiocytosis · HLH · Macrophage activation syndrome · MAS · Cytokine storm syndrome · Hemophagocytic syndrome · Secondary HLH · Acquired HLH · Familial HLH · FHL · Hyperferritinaemic syndrome
Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) — a life-threatening hyperinflammatory syndrome caused by uncontrolled T-cell and macrophage activation resulting in a cytokine storm (IFN-gamma, IL-6, IL-18, TNF-alpha, IL-1beta). Presents with: prolonged fever, cytopenias (bi- or trilineage), hepatosplenomegaly, lymphadenopathy, hyperferritinaemia (10,000 ug/L), hypofibrinogenaemia, hypertriglyceridaemia, transaminitis, coagulopathy, and multi-organ failure. Classified as: (1) primary/genetic HLH (FHL, perforin deficiency, infancy), (2) secondary HLH (infection-triggered: EBV, CMV, HIV, SARS-CoV-2; malignancy-triggered: lymphoma, leukaemia; autoimmune-triggered: SLE/MAS, adult-onset Still disease; post-immunosuppression/ICI). Diagnosis: HLH-2004 criteria (5 of 8: fever, splenomegaly, cytopenias x2+, hypertriglyceridaemia/hypofibrinogenaemia, haemophagocytosis on marrow, low NK cell activity, elevated soluble CD25, hyperferritinaemia) OR HScore. Management: (1) treat the trigger (antivirals for EBV, treat malignancy, immunosuppress for autoimmune), (2) suppress cytokine storm — dexamethasone + etoposide (HLH-2004 protocol), emapalumab (anti-IFN-gamma), anakinra (IL-1 receptor antagonist), tocilizumab (anti-IL-6), ruxolitinib (JAK1/2 inhibitor), (3) supportive ICU care (ventilation, vasopressors, RRT, transfusion). Mortality 20-40% (adult secondary HLH); 50-60% if malignancy-triggered.
Checked against its sources on 14 Oct 2026
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Red flags
- Prolonged fever (7+ days) + cytopenias + hepatosplenomegaly + ferritin >10,000 = HLH until proven otherwise — check HLH-2004 criteria
- Ferritin >10,000 ug/L with fever and organ dysfunction is highly suggestive of HLH — adult ferritin is normally <300 ug/L in men, <150 in women
- EBV is the #1 infectious trigger of secondary HLH — check EBV DNA PCR in ALL suspected HLH patients
- T-cell lymphoma is the #1 malignancy trigger — HLH and lymphoma can coexist and masquerade as each other — bone marrow biopsy + lymph node biopsy is essential
- Soluble CD25 (soluble IL-2 receptor) >2400 U/mL = T-cell activation marker = supports HLH diagnosis
- Etoposide (VP-16) is the cornerstone of HLH treatment (HLH-2004 protocol) — but causes cytopenias — dose-reduce in liver dysfunction
- Emapalumab (anti-IFN-gamma) is FDA-approved for refractory primary HLH — IFN-gamma is the key pathogenic cytokine
- DO NOT give broad immunosuppression blindly without searching for malignancy — occult T-cell lymphoma may be driving the HLH and will be missed
Meet the patient
A middle-aged previously well man has had ten days of swinging fevers. He is now confused, jaundiced and needs high-flow oxygen. Ferritin returns markedly raised, platelets low, his spleen is palpable, and broad-spectrum antibiotics have not touched him.[4]
Every registrar reaches for "atypical sepsis" — and the adult HLH guidance warns the phenotype can be indistinguishable from sepsis or multiple organ dysfunction. The examiner's first question is the real one: "What single test made you think of HLH, and what is your first drug?"[4]
References13ShowHide
- [1]Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis Pediatr Blood Cancer, 2007.PMID 16937360
- [2]Henter JI, Samuelsson-Horne A, Aricò M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation Blood, 2002.PMID 12239144
- [3]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.PMID 28935695
- [4]La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults Blood, 2019.PMID 30992265
- [5]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.PMID 24782338
- [6]Allen CE, Yu X, Kozinetz CA, McClain KL Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis Pediatr Blood Cancer, 2008.PMID 18085676
- [7]Selvam S, Tuli A, Yuvasai KP, et al. Predicting Secondary Hemophagocytic Lymphohistiocytosis in Adult Patients with Scrub Typhus and Its Prognostic Significance Indian J Crit Care Med, 2024.PMID 39360205
- [8]Locatelli F, Jordan MB, Allen C, et al. Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis N Engl J Med, 2020.PMID 32374962
- [9]Jacqmin P, Laveille C, Snoeck E, et al. Emapalumab in primary haemophagocytic lymphohistiocytosis and the pathogenic role of interferon gamma: A pharmacometric model-based approach Br J Clin Pharmacol, 2022.PMID 34935183
- [10]Horne A, von Bahr Greenwood T, Chiang SCC, et al. Efficacy of Moderately Dosed Etoposide in Macrophage Activation Syndrome-Hemophagocytic Lymphohistiocytosis J Rheumatol, 2021.PMID 33589555
- [11]Ghonge A, Samperio VM, Hamoud M, Dasanu CA Current outlook on the use of biological agents to improve outcomes in adult secondary hemophagocytic lymphohistiocytosis Expert Opin Biol Ther, 2026.PMID 42334930
- [12]Scholz L, Posch F, Schulz E, et al. Ruxolitinib, IV Immunoglobulin, and High-Dose Glucocorticoids for Critically Ill Adults With Secondary Hemophagocytic Lymphohistiocytosis: A Single-Center Observational Pilot Study. Crit Care Explor, 2024.PMID 38511127
- [13]Georgiadou S, Gatselis NK, Stefos A, et al. Efficient management of secondary haemophagocytic lymphohistiocytosis with intravenous steroids and γ-immunoglobulin infusions World J Clin Cases, 2019.PMID 31750324