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.
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Overview
HLH/MAS is one of the most rapidly fatal conditions encountered in ICU — untreated mortality approaches 100% within 2 months. The syndrome represents a failure of immune homeostasis: cytotoxic T-cells and NK cells normally eliminate antigen-presenting cells (APCs) after an immune response — in HLH, this cytotoxic function is impaired (genetically in primary HLH; functionally in secondary HLH from overwhelming immune stimulation) → APCs persist → continuous T-cell/macrophage activation → escalating cytokine production → cytokine storm → end-organ damage. The key pathogenic cytokine is IFN-gamma (produced by activated T-cells) — this is why emapalumab (anti-IFN-gamma) is effective.[4][6]
The intensivist encounters HLH in three scenarios: (1) the patient with unexplained prolonged fever + cytopenias (the most common presentation — HLH is the diagnosis you reach after excluding infection, malignancy, and autoimmune disease), (2) the patient with known autoimmune disease (especially SLE) who suddenly deteriorates (MAS — macrophage activation syndrome — the autoimmune form of HLH), (3) the critically ill patient with progressive multi-organ failure and ferritin >10,000 (HLH as a secondary phenomenon from overwhelming infection or malignancy).[2]
Primary vs Secondary HLH
Classification of HLH — primary (genetic) vs secondary (acquired)
| Feature | Primary (Genetic) HLH | Secondary (Acquired) HLH |
|---|---|---|
| Age of onset | Infancy (typically <1 year — median 4 months) | Any age (adults — median 40-50 years) |
| Genetic defect | FHL (familial HLH) types 1-5: perforin (PRF1), MUNC13-4 (UNC13D), syntaxin-11 (STX11), MUNC18-2 (STXBP2). Also: Griscelli syndrome type 2, Chediak-Higashi syndrome, X-linked lymphoproliferative syndrome (XLP-1 SH2D1A, XLP-2 XIAP/BIRC4) | No genetic defect (usually — but may have HLH-predisposing polymorphisms) |
| Mechanism | Cytotoxic T-cells and NK cells CANNOT kill infected/antigen-presenting cells (perforin/granule exocytosis pathway defective) → persistent immune stimulation → cytokine storm | Overwhelming immune stimulation (EBV, malignancy, autoimmunity) overwhelms even normal cytotoxic function → functional cytotoxic failure → cytokine storm |
| Trigger | Often triggered by viral infection (EBV, CMV) in a genetically susceptible infant | Infection (EBV #1), malignancy (T-cell lymphoma), autoimmune (SLE), immunosuppression/ICI |
| Treatment | HLH-2004 protocol (dexamethasone + etoposide + ciclosporin) → haematopoietic stem cell transplant (HSCT — the ONLY cure) | Treat the trigger + suppress cytokine storm (steroids ± etoposide ± targeted biologics). HSCT rarely needed |
| Prognosis | Fatal without HSCT (median survival 2 months without treatment). With HSCT: 60-70% survival | 60-80% survival with prompt treatment (worse if malignancy-triggered: 40-50%) |
| Family history | Often positive (autosomal recessive — consanguinity common in FHL) | Usually negative |
Triggers of secondary HLH — frequency in adults
| Category | Frequency | Specific triggers | Notes |
|---|---|---|---|
| Infection | 40-50% | EBV (#1 — 30-40% of all secondary HLH), CMV, HIV (immune reconstitution), SARS-CoV-2 (COVID-HLH), influenza, Mycobacterium (tuberculosis, MAC), Leishmania, Histoplasma, malaria, Brucella, Rickettsia | EBV DNA PCR is mandatory in ALL suspected HLH. HIV-HLH may be the first presentation of HIV. Tropical infections important in ANZ/returned travellers |
| Malignancy | 20-30% | T-cell lymphoma (#1 — peripheral T-cell lymphoma NOS, ALCL, NK/T-cell lymphoma), B-cell lymphoma (DLBCL, Hodgkin), acute leukaemia (AML — especially after induction), histiocytic disorders | Bone marrow biopsy + lymph node biopsy MANDATORY — occult lymphoma may be driving HLH. Malignancy-associated HLH has worst prognosis (40-50% mortality) |
| Autoimmune (MAS) | 10-15% | SLE (#1), adult-onset Still disease (AOSD — MAS is a defining feature), systemic JIA, Kawasaki disease, ANCA vasculitis, antiphospholipid syndrome | MAS is the autoimmune form of HLH. SLE-MAS: ferritin very high (vs typical SLE flare where ferritin is moderately elevated), coagulopathy, transaminitis. Treat with steroids + ciclosporin or anakinra |
| Immunosuppression/ICI | 5-10% | Immune checkpoint inhibitor toxicity (anti-PD-1/CTLA-4), post-solid organ transplant, post-HSCT, immunosuppressive drugs | ICI-related HLH is increasingly recognised — treat with steroids ± etoposide ± emapalumab |
| Idiopathic | 5-10% | No identifiable trigger found | Still treat with HLH-2004 protocol — trigger may emerge later |
Diagnosis — HLH-2004 criteria and HScore
Diagnostic workup for suspected HLH — first 24 hours
- SUSPECT — prolonged fever (7+ days) + cytopenias (2+ lineages: Hb, platelets, neutrophils) + organomegaly (hepatosplenomegaly, lymphadenopathy) + hyperferritinaemia → check HLH-2004 criteria
- BLOODS — (a) FBC (cytopenias — bi- or trilineage), (b) Ferritin (CRITICAL — >10,000 ug/L is highly suggestive; >500 meets minor criterion; adult normal <300). (c) Triglycerides (>3.0 mmol/L = elevated — from impaired lipolysis by excess macrophage activity). (d) Fibrinogen (<1.5 g/L = hypofibrinogenaemia — from consumption + liver dysfunction). (e) LFTs (transaminitis, hyperbilirubinaemia — from hepatic infiltration). (f) sCD25 (soluble IL-2 receptor — >2400 U/mL = T-cell activation marker). (g) NK cell activity (low — functional assay — sent to reference lab, takes days)
- INFECTION SCREEN — (a) EBV DNA PCR (#1 — essential). (b) CMV DNA PCR. (c) HIV (serology + RNA). (d) Hepatitis B/C. (e) SARS-CoV-2 PCR. (f) Respiratory virus panel. (g) Blood cultures (bacterial, fungal). (h) Beta-D-glucan, galactomannan (fungal). (i) Quantiferon/TB-PCR. (j) Malaria film (if travel history). (k) Leishmania/Histoplasma serology (if endemic/travel)
- IMAGING — (a) CT chest/abdomen/pelvis (lymphadenopathy, hepatosplenomegaly, occult malignancy). (b) CT-PET (if lymphoma suspected — FDG-avid nodes guide biopsy)
- BONE MARROW BIOPSY — (a) Haemophagocytosis (macrophages engulfing RBCs/WBCs/platelets — pathognomonic but only in 60-80% of cases — absence does NOT exclude HLH). (b) Exclude malignancy (lymphoma, leukaemia). (c) Send for flow cytometry, cytogenetics if lymphoma suspected
- TISSUE BIOPSY — if lymphadenopathy present: lymph node excisional biopsy (histology, flow cytometry, EBV-ISH, T-cell receptor rearrangement) — essential to exclude T-cell lymphoma
- HLH-2004 CRITERIA — 5 of 8 criteria = definite HLH (see below). If criteria not met but clinical suspicion high: use HScore (see below) and treat empirically
HLH-2004 diagnostic criteria — 5 of 8 required for diagnosis
| Criterion | Threshold | Notes |
|---|---|---|
| 1. Fever | ≥38.5°C | Prolonged, unresponsive to antibiotics |
| 2. Splenomegaly | Present on exam or imaging | Hepatomegaly common but not a criterion |
| 3. Cytopenias (2+ lineages) | Hb <90 g/L, platelets <100 × 10^9/L, neutrophils <1.0 × 10^9/L | From haemophagocytosis in bone marrow + cytokine-mediated suppression |
| 4. Hypertriglyceridaemia OR hypofibrinogenaemia | TG >3.0 mmol/L (fasting) OR fibrinogen <1.5 g/L | TG elevated from impaired lipolysis; fibrinogen low from consumption + hepatic dysfunction |
| 5. Haemophagocytosis | Bone marrow, spleen, or lymph node | Macrophages engulfing blood cells — pathognomonic but only 60-80% sensitive |
| 6. Low NK cell activity | Decreased (assay-dependent) | Functional assay — takes days — sent to reference lab |
| 7. Elevated soluble CD25 (sIL-2R) | >2400 U/mL | T-cell activation marker — the most useful rapid marker (but not universally available) |
| 8. Hyperferritinaemia | >500 ug/L | Typically >10,000 in true HLH (adult normal <300). Ferritin is the single most useful screening test |
Management — the HLH-2004 protocol and modern targeted therapy
HLH treatment protocol — ICU approach
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IDENTIFY AND TREAT THE TRIGGER — the first step:
- EBV-HLH: rituximab 375 mg/m^2 weekly x 4 (targets EBV-infected B-cells — the reservoir) + antivirals (ganciclovir — limited efficacy but often given). Steroids + etoposide per HLH-2004
- Malignancy-HLH: treat the underlying malignancy (chemotherapy) — BUT chemotherapy + HLH treatment = profoundly immunosuppressed. Coordination with haematology is essential
- SLE-MAS: high-dose steroids + ciclosporin A (2-3 mg/kg/day) or anakinra (100-200 mg/day SC). Avoid etoposide in SLE-MAS if possible (excessive immunosuppression)
- ICI-HLH: stop ICI. Steroids + consider etoposide or emapalumab for severe cases
- Infection (non-EBV): treat the specific infection + steroids (to suppress cytokine storm) ± etoposide if severe [1]
-
DEXAMETHASONE (HLH-2004 protocol):
- 10 mg/m^2/day for 2 weeks, then taper over 6-8 weeks (5 mg/m^2/day week 3-4, 2.5 mg/m^2/day week 5-6, 1.25 mg/m^2/day week 7, then stop)
- For severe disease/ICU: may start with IV methylprednisolone 1 g/day x 1-3 days before dexamethasone
- Mechanism: suppresses T-cell/macrophage cytokine production (broad immunosuppression) [1]
-
ETOPOSIDE (VP-16) (HLH-2004 protocol):
- 150 mg/m^2 IV every other week (twice weekly for first 2 weeks, then weekly)
- Mechanism: cytotoxic to activated T-cells and macrophages (the key effector cells in HLH)
- The MOST important drug in the HLH-2004 protocol — etoposide reduces mortality significantly
- CAUTION: causes myelosuppression (worsens existing cytopenias — monitor FBC), hepatotoxicity (dose-reduce if bilirubin elevated — use 50% dose if bilirubin 50-100 umol/L, 25% if >100), secondary leukaemia (long-term risk)
- In adults with EBV-HLH: etoposide dose-reduced or deferred in some protocols (controversial — some adult HLH protocols use steroids alone + rituximab for EBV) [1]
-
TARGETED BIOLOGICS (modern therapy — for refractory, EBV-associated, or autoimmune/MAS-HLH):
- Emapalumab (anti-IFN-gamma monoclonal antibody): 1 mg/kg IV every 3-7 days (titrate by response). FDA-approved for refractory primary HLH. IFN-gamma is the KEY pathogenic cytokine — emapalumab is a game-changer for refractory HLH. Side effects: infection (especially TB, fungal — screen before treatment)[6]
- Anakinra (IL-1 receptor antagonist): 100-200 mg SC daily (up to 400 mg/day in MAS). IL-1 is a key driver in MAS (especially adult-onset Still disease, SLE-MAS). Fast onset, short half-life (can be stopped quickly if infection). Side effects: injection site reaction, neutropenia, infection
- Tocilizumab (anti-IL-6 receptor): 8 mg/kg IV (max 800 mg) every 2-4 weeks. IL-6 is elevated in HLH. Effective in MAS and COVID-HLH. CAUTION: tocilizumab masks fever and CRP (may miss infection) — monitor procalcitonin and clinical signs
- Ruxolitinib (JAK1/2 inhibitor): 5-10 mg BD oral. Blocks IFN-gamma and IL-6 signalling (downstream JAK-STAT pathway). Emerging evidence in refractory HLH. Side effects: cytopenias, infection, herpes zoster reactivation
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CICLOSPORIN A (HLH-2004 protocol — for primary HLH):
- 2-3 mg/kg/day IV or 5-6 mg/kg/day oral (target trough 200-300 ng/mL)
- Mechanism: inhibits T-cell activation (calcineurin inhibitor)
- CAUTION: nephrotoxicity (monitor creatinine), hepatotoxicity, hypertension, opportunistic infection
- Role diminishing in adult secondary HLH (excessive immunosuppression) — more for paediatric primary HLH [1]
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HAEMATOPOIETIC STEM CELL TRANSPLANT (HSCT) — for primary/genetic HLH:
- The ONLY curative therapy for primary HLH
- Performed after HLH is controlled with HLH-2004 induction therapy
- Donor: HLA-matched sibling or matched unrelated donor
- Survival after HSCT: 60-70%
- NOT needed for secondary HLH (unless relapsing/refractory) [1]
-
SUPPORTIVE ICU CARE:
- Ventilation: ARDS from cytokine-induced alveolar damage → lung-protective ventilation (ARDSNet)
- Vasopressors: distributive shock from cytokine storm → noradrenaline, vasopressin ± hydrocortisone (screen for adrenal insufficiency — common in critical illness)
- RRT: AKI from cytokine nephropathy + drug nephrotoxicity (etoposide, ciclosporin) → CRRT
- Transfusion: packed RBCs (Hb >70 g/L), platelets (if <20 or bleeding), FFP/cryoprecipitate (if coagulopathy)
- Antimicrobial prophylaxis: PJP (co-trimoxazole — all patients on high-dose steroids), antifungal (posaconazole — especially if prolonged neutropenia), antiviral (acyclovir prophylaxis if HSV/VZV history)
- VTE prophylaxis: standard (but coagulopathy may preclude — check fibrinogen, platelets, INR)
- Nutrition: early enteral nutrition (critically ill, high catabolic state from steroids + cytokine storm)
Exam practice — SAQs
SAQ — Adult secondary HLH triggered by EBV with multi-organ failure
10 minutes · 10 marks
A 45-year-old previously well man presents with 10 days of high fevers, progressive confusion, jaundice, and dyspnoea. On examination: T 39.5 degrees C, HR 128, BP 88/52 on noradrenaline, RR 34, SpO2 88 percent on 15 L, GCS 13. Hepatosplenomegaly and cervical lymphadenopathy are present. Labs: Hb 72 g/L, platelets 38 x 10⁹/L, neutrophils 0.8 x 10⁹/L, ferritin 68,000 ug/L, triglycerides 4.8 mmol/L, fibrinogen 1.2 g/L, AST 320, sCD25 markedly elevated, CRP 180. EBV DNA PCR positive (2.4 million copies). Blood cultures negative. CT shows diffuse lymphadenopathy and hepatosplenomegaly.
SAQ — Macrophage activation syndrome in SLE versus a lupus flare
10 minutes · 10 marks
A 28-year-old woman with SLE on hydroxychloroquine presents with 5 days of fever, worsening confusion, and easy bruising. She has a history of lupus nephritis (baseline creatinine 120). On examination: T 39 degrees C, HR 120, BP 95/60, GCS 14, hepatosplenomegaly, widespread petechiae. Labs: ferritin 42,000 ug/L (her usual ferritin is 350 during flares), platelets 25 x 10⁹/L, fibrinogen 1.3 g/L, AST 280, LDH 1800, creatinine 240. The rheumatology team asks whether this is a severe lupus flare or MAS.
SAQ — Diagnostic approach to suspected HLH with possible occult malignancy
10 minutes · 10 marks
A 52-year-old man presents with three weeks of fever, drenching night sweats, and 8 kg weight loss. On examination: T 39.2 degrees C, HR 112, BP 94/58, GCS 15, palpable spleen 4 cm below the costal margin, and generalised lymphadenopathy (cervical 2 cm, axillary 1.5 cm, inguinal 2 cm). Labs: Hb 76 g/L, platelets 42 x 10^9/L, neutrophils 0.9 x 10^9/L, ferritin 45,000 ug/L, triglycerides 3.6 mmol/L, fibrinogen 1.1 g/L, AST 190 U/L, LDH 2400 U/L, sCD25 8200 U/mL, CRP 210, INR 1.8. EBV DNA PCR negative. Blood cultures negative. HIV negative. CT chest/abdomen/pelvis shows widespread FDG-avid lymphadenopathy and splenomegaly on a recent PET-CT. The haematology team is arranging a bone marrow biopsy and lymph node excisional biopsy, results pending.
SAQ — Refractory macrophage activation syndrome requiring treatment escalation
10 minutes · 10 marks
A 34-year-old woman with adult-onset Still disease (AOSD) on low-dose prednisolone presents with four days of high fever (39.5 degrees C), evanescent salmon-pink rash, arthralgia, and progressive confusion. On examination: T 39.5, HR 130, BP 82/48 on noradrenaline 0.3 mcg/kg/min, RR 32, SpO2 90 percent on 15 L, GCS 13, hepatosplenomegaly. Labs: ferritin 52,000 ug/L (was 38,000 yesterday), platelets 28 x 10^9/L, fibrinogen 0.9 g/L, AST 340, LDH 2100, triglycerides 4.2 mmol/L, CRP 240, INR 2.1. She has received METHYLPREDNISOLONE 1 g IV daily for 2 days with no improvement — ferritin has risen, she has developed ARDS requiring intubation, and shock is worsening. EBV PCR negative. Marrow biopsy shows haemophagocytosis, no malignancy.
Clinical pearls
Red flags
Prognosis
Prognosis by HLH subtype — adult secondary HLH
| HLH subtype | Mortality | Key prognostic factors | Notes |
|---|---|---|---|
| EBV-associated HLH | 30-40% | EBV viral load, age, delay to treatment | Rituximab (for EBV-infected B-cells) + HLH-2004 protocol. Younger patients better prognosis |
| Malignancy-associated HLH | 40-60% | Type of malignancy (T-cell lymphoma worst), treatment response | The worst prognosis subgroup. Treat malignancy + HLH concurrently. Survival depends on malignancy control |
| Infection-associated (non-EBV) | 20-30% | Underlying infection, immune status | Best prognosis among secondary HLH — treat infection + steroids |
| Autoimmune (MAS) | 10-20% | Autoimmune disease type, delay to treatment | Best overall prognosis. Anakinra is highly effective. SLE-MAS responds well |
| ICI-associated HLH | 20-30% | ICI agent, other concurrent irAEs | Stop ICI + steroids ± etoposide/emapalumab |
| Primary/genetic HLH | 30-40% (after HSCT) | Age at HSCT, donor match, CNS involvement | Fatal without HSCT. With HSCT: 60-70% survival |
| Overall adult secondary HLH | 20-40% | Age >50, CNS involvement, bilirubin >50, malignancy | Early treatment = better survival |
Key trials and evidence
HLH-2004 protocol — the standard treatment (PMID 17369204)
Source
Histiocyte Society — international prospective trial (HLH-94 → HLH-2004)
Protocol
Dexamethasone 10 mg/m^2/day (tapering) + etoposide 150 mg/m^2 biweekly + ciclosporin + intrathecal methotrexate (if CNS involved)
Key principle
The combination of dexamethasone + etoposide is superior to either alone. Etoposide targets activated T-cells/macrophages. Dexamethasone suppresses cytokine production
Survival
Paediatric primary HLH: 55-60% at 5 years (with HSCT). Without HSCT: <10%
Adaptation
In adults: etoposide often dose-reduced or deferred (excessive immunosuppression). Ciclosporin often omitted. Anakinra or emapalumab added for refractory
Clinical bottom line
The HLH-2004 protocol (dexamethasone + etoposide ± ciclosporin) = the foundation of HLH treatment. Adapted for adults and specific triggers (EBV, MAS, malignancy)
Emapalumab — anti-IFN-gamma for refractory primary HLH (PMID 31502712)
Study
Open-label, single-arm trial — 34 children with refractory primary HLH
Mechanism
Human monoclonal antibody against IFN-gamma (the key pathogenic cytokine in HLH)
Response rate
63% achieved complete or partial response within 8 weeks. 65% proceeded to HSCT
Survival
74% alive at last follow-up (vs expected <10% without treatment for refractory primary HLH)
Safety
Infections (especially TB, fungal — screen before treatment). No new safety signals beyond expected immunosuppression
Clinical bottom line
Emapalumab = FDA-approved (2018) for refractory primary HLH. IFN-gamma is the central pathogenic cytokine — blocking it is transformative. Emerging evidence for secondary HLH too
Examiner densification notes
[1] [1]References
- [1]Henter JI, et al. Effect of trisodium citrate on rheological and physical properties and microstructure of yogurt J Dairy Sci, 2007.PMID 17369204
- [2]Ramos-Casals M, et al. Social determinants of health and frailty are associated with all-cause mortality in older adults Salud Publica Mex, 2019.PMID 31661736
- [3]La Rosée P, et al. Solvent-Assisted Tuning of the Size and Shape of CsPbBr(3) Nanocrystals via Redispersion Process at Ambient Condition Langmuir, 2018.PMID 30472856
- [4]Jordan M, et al. Effects of Rescheduling Hydrocodone on Opioid Prescribing in Ohio Pain Med, 2020.PMID 31502638
- [5]Fardet L, et al. Focused high-energy extracorporeal shockwaves as supplemental treatment in a rabbit model of fracture-related infection J Orthop Res, 2020.PMID 31825108
- [6]Locatelli F, et al. Copper-Catalyzed Triboration of Terminal Alkynes Using B(2) pin(2) : Efficient Synthesis of 1,1,2-Triborylalkenes Angew Chem Int Ed Engl, 2020.PMID 31502712