Adult macrophage activation syndrome and secondary HLH

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Suspect HLH when apparent sepsis or inflammatory flare is unusually persistent, progressive and cytopenic. Record fever curve, blood-count trajectory, ferritin rate of change, liver and coagulation dysfunction, spleen size, neurological state and organ support. A patient can have infection and HLH together; forcing an early either-or choice causes delay in both antimicrobial and immune treatment.

Macrophage activation syndrome is most familiar in adult-onset Still disease, systemic juvenile idiopathic arthritis and lupus. Warning change includes sustained rather than quotidian fever, abrupt platelet decline, new neutropenia, hepatitis, triglyceride rise and fibrinogen fall. ESR may fall because it depends on fibrinogen even as CRP, ferritin and organ injury worsen, so a lower ESR is not reassurance.

Send an immediate panel and repeat it according to instability: FBC with film and reticulocytes, ferritin, fasting triglycerides where feasible, fibrinogen, PT, APTT, D-dimer, liver profile, LDH, renal profile, electrolytes, CRP, ESR, lactate and haemolysis tests. Group and save serum and involve transfusion medicine if coagulation or cytopenia is severe. Trends across six to twelve hours can be diagnostically decisive.

HLH-2004 comprises fever, splenomegaly, cytopenias in at least two lineages, hypertriglyceridaemia or hypofibrinogenaemia, haemophagocytosis, low NK function, ferritin and raised soluble CD25; five of eight meets its protocol definition. HScore combines immune status, temperature, organomegaly, blood counts, ferritin, triglyceride, fibrinogen, AST and marrow findings. Use both as structured evidence, not permission slips to delay care.

The trigger investigation runs beside resuscitation. Obtain repeated blood cultures and infection-site samples, EBV and CMV PCR, HIV and hepatitis testing and exposure-directed tuberculosis, fungal, parasitic and respiratory studies. Interpret viral load with immune status. Broad antimicrobial cover follows local severe-sepsis and immunocompromised-host policy and should not be withheld because immune treatment is also required.

Search malignancy deliberately with blood film, LDH, CT neck-to-pelvis or FDG-PET when stable, marrow aspirate and trephine with flow, cytogenetics and microbiology, and architecture-preserving node or organ biopsy. Steroid may obscure lymphoma, but life-threatening HLH cannot wait indefinitely for ideal tissue; haematology should record which sample can safely be protected before treatment.

Bone marrow is valuable for lymphoma, leukaemia, infection and cytopenia evaluation, not as a stand-alone HLH gold standard. Haemophagocytosis can be patchy or absent early and can appear without HLH. Specialist soluble CD25, NK-cell function, perforin expression and genetic panels help difficult, recurrent, familial or young-adult cases but turnaround is too slow for the first emergency decision.

Initial care includes critical-care physiology, oxygen or ventilation, cautious fluid and vasoactive support, renal replacement when indicated, glucose and electrolyte correction and blood products guided by bleeding, procedures and coagulation. Avoid reflex platelet or fibrinogen targets divorced from the clinical situation. Discuss antimicrobial prophylaxis, tumour lysis and fertility when cytotoxic treatment becomes likely.

In rheumatic MAS, IV methylprednisolone 500–1000 mg daily for three days is a common organ-threatening induction followed by oral taper. Anakinra is often added early when severe or steroid-resistant and can be given subcutaneously or intravenously under specialist protocols. Its short half-life is useful in unstable infection-risk settings, but dose and interval need renal and critical-care review.

For severe adult HLH, an HLH-94-based approach remains important: dexamethasone 10 mg/m² daily initially with protocol taper and etoposide 150 mg/m² twice weekly during the first two weeks then weekly. Do not reproduce a protocol from memory at bedside; haematology verifies body-surface dose, renal and hepatic modification, cytopenia context and the urgency of etoposide, particularly in EBV- or lymphoma-associated disease.

Trigger treatment determines durable control. Give lymphoma-directed chemotherapy, appropriate antimicrobial therapy and source control, or active rheumatic-disease suppression. Rituximab may reduce EBV-infected B-cell burden; IV immunoglobulin can be adjunctive in selected infection-associated or immune-mediated disease. Refractory, relapsing or genetically driven HLH needs a transplant-centre plan and potentially allogeneic stem-cell transplantation.

Assess response at least daily during instability using temperature, vasoactive and respiratory needs, mental state, FBC, fibrinogen, coagulation, liver and kidney function and ferritin. Failure to improve prompts renewed tissue search, antimicrobial adequacy, occult malignancy, CNS disease, drug toxicity and escalation. Handover must name the trigger confidence, immune regimen, infection protection and next decision threshold.

Key points

HLH is a time-critical hyperinflammatory syndrome, not a single test result; macrophage activation syndrome is the rheumatic-disease context of secondary HLH.
The key pattern is unremitting fever plus worsening cytopenias, liver injury, splenomegaly, hypertriglyceridaemia, falling fibrinogen, coagulopathy and a rapidly rising ferritin.
First-line action is simultaneous: stabilise organ failure, culture and treat infection, calculate evolving probability, protect marrow or node tissue, and discuss immune treatment immediately.
HLH-2004 supports diagnosis when five of eight features are present, but was developed for paediatric protocols; HScore estimates adult reactive-HLH probability but neither is a gold-standard rule-out test.
A very high ferritin supports the syndrome but is less specific in adults than children. Serial direction linked to blood counts, fibrinogen, triglycerides and organ function is more useful.
Bone-marrow haemophagocytosis may be absent early and occurs in sepsis, transfusion and critical illness; never delay treatment solely to repeat a negative marrow.
Search triggers in parallel: EBV and other infection, T/NK or B-cell lymphoma, leukaemia, Still disease, lupus, immunodeficiency, transplant and treatment-associated syndromes.
Rheumatic MAS commonly receives immediate high-dose glucocorticoid and early specialist anakinra; severe adult HLH often needs dexamethasone and etoposide tailored to trigger and organ function.
EBV-associated disease may require rituximab when infected B cells are implicated, but rituximab is an adjunct and does not replace T-cell-directed HLH control or lymphoma therapy.
Clinical improvement requires fever, haemodynamic, neurological, blood-count, fibrinogen, liver and ferritin recovery; a falling ferritin alone does not prove control.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Infection-triggered disease

EBV and other herpesviruses, HIV, hepatitis, tuberculosis, leishmaniasis and invasive fungal or bacterial infection can drive HLH; geography, immune status and treatment exposures determine the search.

Malignancy-associated disease

T-cell and NK-cell lymphomas are particularly important, but B-cell lymphoma, leukaemia and other cancers can trigger cytokine activation before the malignancy is obvious.

Rheumatic macrophage activation

Adult-onset Still disease, systemic juvenile idiopathic arthritis and systemic lupus are principal inflammatory settings; infection or a medicine can act as a second hit during an apparent flare.

Genetic, immune and treatment predisposition

Hypomorphic cytotoxic-pathway variants can present in adults, while transplant, immunodeficiency, CAR-T therapy, checkpoint inhibition and selected medicines create distinct hyperinflammatory syndromes.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Failed cytotoxic termination
Impaired or overwhelmed NK-cell and cytotoxic T-cell killing allows antigen-presenting targets and activated lymphocytes to persist instead of closing the immune response.
2
Self-amplifying cytokine loop
Interferon-gamma, interleukins, TNF and chemokines continuously activate macrophages and lymphocytes, producing fever, endothelial leak, vasoplegia and tissue injury.
3
Blood-cell consumption and suppression
Activated macrophages may engulf blood cells, while cytokines suppress marrow and shorten cell survival; haemophagocytosis is therefore neither necessary nor specific.
4
Hepatic and coagulation failure
Liver inflammation reduces synthesis and clearance, macrophage activation consumes fibrinogen, and endothelial injury promotes disseminated coagulation, bleeding and thrombosis.
5
Multiorgan inflammatory injury
Spleen, liver, marrow, lung, kidney, brain and heart become involved through infiltrating cells, cytokines, infection and shock, making trajectory more important than one laboratory value.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Dynamic laboratory constellationRed flag

Falling platelets and neutrophils with rising ferritin, AST and triglycerides and falling fibrinogen is a high-risk evolving signature even before five HLH-2004 criteria are complete.

Rheumatic MAS transitionRed flag

Still or lupus activity becomes sustained fever, cytopenia, coagulopathy and hepatitis; ESR may fall as fibrinogen is consumed despite clinical deterioration.

Malignancy-associated pattern

Nodes, spleen enlargement, disproportionate LDH, B symptoms, abnormal film or focal PET activity should accelerate lymphoma-directed marrow and tissue sampling.

Neurological involvementRed flag

Confusion, irritability, seizure, meningism or focal deficit can represent CNS inflammation, infection, haemorrhage or metabolic failure and changes immediate support.

Haemophagocytosis caveat

Macrophages containing blood cells support the context but may be absent early and are seen in critical illness without HLH; the finding never stands alone.

Adult genetic clue

Recurrent episodes, family history, unusual infections, young presentation or persistent disease despite trigger control warrants cytotoxic-pathway and immunology assessment.

Red flags requiring action

Persistent high fever with shock, hypoxaemia, encephalopathy, severe hepatitis, acute kidney injury or lactate rise requires immediate critical-care review and simultaneous sepsis and HLH treatment.
A steep ferritin rise accompanied by falling platelets, neutrophils or haemoglobin, rising triglycerides and falling fibrinogen is more concerning than any isolated threshold.
Bleeding, purpura, line ooze, prolonged clotting, low fibrinogen or rapidly rising D-dimer suggests consumptive coagulopathy and requires urgent blood-product and cause-specific planning.
Lymphadenopathy, splenomegaly, weight loss, night sweats, LDH rise, abnormal film or focal PET uptake raises lymphoma-associated HLH and makes protected marrow or tissue urgent.
Seizure, confusion, focal deficit, meningism or reduced consciousness can reflect CNS HLH, infection, metabolic failure or treatment toxicity and needs immediate neurological assessment.
A patient with Still disease, systemic JIA or lupus who develops disproportionate fever, cytopenia, hepatitis and coagulopathy may have MAS even when CRP remains high and ESR paradoxically falls.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Immediate repeated HLH panelFirst step
Why
Measure syndrome trajectory and organ threat.
Interpretation and limitations
Repeat FBC and film, ferritin, triglycerides, fibrinogen, coagulation, AST and liver profile, LDH, renal profile, CRP and ESR; direction and rate of change outweigh an isolated result.
02
HLH-2004 and HScore
Why
Structure probability without creating delay.
Interpretation and limitations
Document each component and missing variable. Five HLH-2004 criteria or a high HScore supports action, but a subthreshold score does not safely exclude early rapidly evolving disease.
03
Infection screen
Why
Find a treatable trigger and protect immunosuppression.
Interpretation and limitations
Obtain cultures, EBV and CMV PCR, HIV and hepatitis tests and exposure- or immune-status-directed TB, fungal, parasitic and respiratory sampling before therapy where this causes no dangerous delay.
04
Marrow and tissue
Why
Identify lymphoma, leukaemia, infection and alternative marrow failure.
Interpretation and limitations
Request aspirate, trephine, flow, cytogenetics and relevant microbiology; biopsy an accessible node or lesion for architecture. Haemophagocytosis is supportive but neither required nor specific.
05
Cross-sectional and metabolic imaging
Why
Locate occult cancer, infection and safe tissue.
Interpretation and limitations
Use contrast CT chest, abdomen and pelvis initially when stable; add FDG-PET through the lymphoma or inflammatory MDT when it will guide a target or response.
06
Specialist immune tests
Why
Resolve recurrent, familial or diagnostically difficult disease.
Interpretation and limitations
Send soluble CD25, NK-cell function, perforin or degranulation assays and genetic testing with the specialist laboratory, but never await these to treat unstable probable HLH.
07
Neurological assessment
Why
Separate CNS HLH, infection, bleeding and metabolic injury.
Interpretation and limitations
Perform urgent brain imaging before lumbar puncture when indicated; CSF cell count, protein, glucose, culture, PCR, cytology and flow follow only when coagulation and physiology make sampling safe.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Sepsis with disseminated coagulation

Severe infection can produce fever, shock, cytopenia, ferritin elevation and haemophagocytosis and can also trigger HLH; clinicians often need to treat both processes simultaneously.

Acute liver failure

Viral, toxic, ischaemic and autoimmune hepatitis causes coagulopathy, hypoglycaemia and ferritin release; triglyceride, cytopenia, spleen, trigger and dynamic immune pattern refine probability.

Thrombotic microangiopathy

TTP, complement-mediated HUS and malignant-hypertension TMA cause thrombocytopenia and organ injury; schistocytes, haemolysis, ADAMTS13 and coagulation profile distinguish them urgently.

Occult haematological malignancy

Lymphoma or leukaemia may independently cause fever, cytopenia, nodes and LDH elevation while also driving HLH, so identifying cancer is trigger diagnosis rather than exclusion.

Inflammatory and endocrine crises

Catastrophic antiphospholipid syndrome, severe Still or lupus flare, adrenal crisis, thyroid storm and drug hypersensitivity overlap clinically and require targeted bedside and laboratory separation.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Emergency first hourTreat physiology, infection and hyperinflammation in parallelFirst stepPersistent fever combines with cytopenia, coagulopathy, hepatitis, shock or neurological decline.

1Call haematology, critical care, infection and the relevant rheumatology or oncology team; stabilise airway, circulation, glucose, coagulation and failing organs.
2Send the complete repeated HLH panel, cultures and viral PCR and protect marrow, blood and accessible tissue samples without allowing sampling to postpone life-saving care.
3Start credible antimicrobial coverage and agree an immediate immune-treatment threshold from trajectory, trigger and organ threat rather than waiting for every criterion.

02Trigger sequenceSearch infection, cancer and rheumatic disease togetherInitial probability supports secondary HLH or MAS.

1Map exposures, immune state, medicines and rheumatic phenotype; test EBV, CMV, HIV, hepatitis and targeted bacterial, mycobacterial, fungal or parasitic causes.
2Perform film, marrow, CT or PET and architecture-preserving biopsy for occult lymphoma or leukaemia, prioritising T-cell and NK-cell disease.
3Treat the identified trigger while revisiting dual triggers whenever response is incomplete.

03Rheumatic MAS first-lineSuppress cytokine activation earlyFirst lineStill disease, systemic JIA or lupus phenotype dominates and organ-threatening MAS is probable.

1Give specialist IV methylprednisolone induction while covering credible infection and monitoring haemodynamics, glucose, mental state and coagulation.
2Add anakinra early for severe or inadequately responsive MAS, selecting SC or IV route and renal-adjusted interval through the commissioned protocol.
3EscalationEscalate with haematology if organ failure or laboratory trajectory persists because etoposide-based HLH treatment may still be required.

04Severe or refractory HLHUse trigger-adapted HLH therapyAdult disease is severe, malignancy- or EBV-associated, progressive or unresponsive to initial MAS treatment.

1Start verified dexamethasone and etoposide protocol with hepatic, renal, marrow, antimicrobial, tumour-lysis and fertility safeguards.
2Add lymphoma chemotherapy, EBV-directed rituximab or selected IV immunoglobulin only when the trigger and multidisciplinary plan support it.
3Refer early to an HLH and transplant centre for refractory, recurrent or genetic disease rather than waiting for multiple failed rescue courses.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

Rapid first-line immune suppression for severe MAS while triggers are treated and further therapy is arranged.

Methylprednisolone intravenous pulse

For organ-threatening rheumatic MAS, a common specialist regimen is 500–1000 mg intravenously once daily for three days, followed by an oral glucocorticoid plan.

Take cultures when feasible, treat infection concurrently, and monitor glucose, blood pressure, rhythm, mental state, gastrointestinal and fluid complications.

Early cytokine blockade for severe rheumatic MAS and selected secondary HLH, often with glucocorticoid rather than after prolonged steroid failure.

Anakinra

A specialist severe-MAS regimen commonly starts 100 mg subcutaneously or intravenously every six to twelve hours, then adjusts dose and interval to response, body size and renal clearance.

Use only within specialist protocol; screen and treat infection, adjust in major renal impairment, monitor neutrophils and liver tests, and recognise that high-dose and IV use are off-label.

CNS-penetrant glucocorticoid backbone for severe adult HLH, particularly when etoposide-based treatment is selected.

Dexamethasone

HLH-94 induction starts 10 mg/m² orally or intravenously daily for two weeks, then 5 mg/m² for two weeks, 2.5 mg/m² for two weeks, 1.25 mg/m² for one week and a final taper.

Haematology verifies protocol and route; monitor infection, glucose, mental state, muscle, gastrointestinal and adrenal toxicity and adapt if trigger-specific chemotherapy supplies steroid.

Rapid control of activated T-cell and macrophage drive in severe, progressive, EBV- or malignancy-associated HLH.

Etoposide

HLH-94 uses 150 mg/m² intravenously twice weekly for the first two weeks, then once weekly to week eight; adult timing and dose are modified by liver, kidney, marrow and trigger.

Specialist cytotoxic prescribing only; address myelosuppression, infection, mucositis, hepatic and renal dose modification, tumour lysis, infertility and secondary malignancy.

Adjunct in selected infection-associated, immune-mediated or antibody-deficient secondary HLH; it is not sufficient for rapidly progressive malignancy-associated disease.

Intravenous immunoglobulin

A selected adjunctive course is 2 g/kg total, usually divided over two to five days with dose based on local protocol and ideal or adjusted weight where required.

Assess thrombosis, hyperviscosity, renal and fluid risk, choose formulation and rate carefully and do not let infusion delay trigger-directed therapy.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Refractory multiorgan failure

Vasoplegic shock, respiratory failure, acute kidney injury, myocarditis and hepatic failure can progress despite initial antimicrobial and glucocorticoid treatment.

Consumptive bleeding and thrombosis

Hypofibrinogenaemia, thrombocytopenia, endothelial injury and DIC produce gastrointestinal, pulmonary, intracranial or line bleeding alongside clinically important thrombosis.

Opportunistic and uncontrolled infection

The original pathogen, neutropenia, barrier failure and combined high-dose immune therapy create major viral, fungal and bacterial risk.

Neurological disability

Seizures, encephalopathy, focal inflammation, haemorrhage and critical illness can leave cognitive, motor or epileptic sequelae after systemic control.

Relapse or fatal trigger persistence

Uncontrolled lymphoma, persistent EBV, inherited cytotoxic dysfunction or undertreated inflammatory disease can reactivate HLH and prompt chemotherapy or transplant pathways.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

During instability review temperature, mental state, bleeding, fluid balance and organ support continuously and repeat FBC, fibrinogen, coagulation, ferritin, liver, renal and metabolic measures at least daily or more often.
Judge response as a bundle: defervescence, lower support needs, recovering blood counts and fibrinogen, improving liver and coagulation and a sustained ferritin fall.
Track pathogen load, cultures, antimicrobial exposure and new infection because fever suppression after immune treatment can obscure uncontrolled infection.
Repeat marrow, node imaging or PET according to the malignancy plan; apparent HLH control without trigger control is not durable remission.
Monitor each drug's marrow, liver, renal, infection, metabolic, reproductive and infusion toxicities and ensure dose changes are communicated across ICU, haematology and rheumatology.
After recovery document trigger confidence, relapse signals, genetic indication, vaccine and prophylaxis plan, organ rehabilitation and named HLH or transplant follow-up.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Trajectory outranks threshold

A ferritin of 500 is deliberately sensitive in HLH-2004 but nonspecific in adults; rapid multi-variable deterioration carries more meaning than one dramatic number.

Sepsis and HLH coexist

Infection can be both mimic and trigger, so antimicrobial and immune treatments may need to begin together rather than sequentially.

Marrow is not a veto

Absent haemophagocytosis does not exclude HLH and abundant haemophagocytosis does not prove it; marrow's greatest value is finding cancer or infection.

A falling ESR may be dangerous

Because erythrocyte sedimentation depends partly on fibrinogen, consumptive hypofibrinogenaemia can lower ESR during worsening macrophage activation.

Etoposide timing can matter

In severe EBV- and malignancy-associated disease, excessive hesitation over cytopenia can leave the cytokine-driving lymphocyte population untreated.

The trigger owns long-term outcome

Suppressing the inflammatory loop creates time, but cure depends on controlling lymphoma, infection, rheumatic disease or inherited cytotoxic failure.

11Common pitfallsFrequent interpretation and management errors.

01
Waiting for five HLH-2004 criteria, a very high ferritin or positive marrow while shock and coagulation worsen.
02
Treating the case as either sepsis or HLH when infection may have triggered the immune syndrome and both need immediate therapy.
03
Calling haemophagocytosis diagnostic and abandoning lymphoma, leukaemia, infection and transfusion-related explanations.
04
Assuming a lower ESR means Still-associated inflammation is improving without checking falling fibrinogen and platelets.
05
Giving prolonged glucocorticoid alone for probable lymphoma-associated HLH without protecting tissue or discussing early etoposide and cancer treatment.
06
Following ferritin alone and overlooking ongoing CNS disease, coagulopathy, cytopenia, organ support or persistent trigger.