Haemophagocytic Lymphohistiocytosis (HLH)

🧠 HLH is a rare but life-threatening hyperinflammatory syndrome caused by uncontrolled activation of cytotoxic T-cells and macrophages. It can mimic sepsis, malignancy, autoimmune disease or liver failure, so it is easily missed. Consider HLH in a deteriorating patient with persistent fever, cytopenias, organ dysfunction, coagulopathy and very high ferritin, especially if they are not improving with standard treatment.

📖 Overview

• HLH is a severe disorder of immune regulation causing excessive cytokine release and macrophage activation.
• The immune system becomes unable to “switch off”, causing a cytokine storm and multi-organ damage.
• It may be primary / familial or secondary / acquired.
• In adults, HLH is usually secondary to infection, malignancy, autoimmune disease or immunosuppression.
• It is a medical emergency requiring urgent haematology input.

🧬 Pathophysiology

In HLH, cytotoxic T-cells and natural killer cells fail to clear activated immune cells properly. This causes persistent immune stimulation, macrophage activation and excessive cytokine release. Activated macrophages may engulf red cells, white cells and platelets in the bone marrow, spleen or lymph nodes — this is called haemophagocytosis. However, haemophagocytosis is not always present early and its absence does not exclude HLH.

🧒 Primary HLH

• Usually presents in infancy or childhood.
• Caused by inherited defects in cytotoxic lymphocyte or NK-cell function.
• May be triggered by infection, especially viral illness.
• Often requires specialist immunology / haematology management.
• Some patients require haematopoietic stem cell transplantation.

👨‍⚕️ Secondary HLH

• More common in adults.
• Occurs as a complication of another inflammatory, infective or malignant process.
• May occur in previously well patients or in immunocompromised patients.
• Requires treatment of both the hyperinflammation and the underlying trigger.

⚠️ Common Triggers

🚨 When to Suspect HLH

• Persistent fever despite appropriate antimicrobial treatment.
• Unexplained cytopenias affecting two or more blood cell lines.
• Very high or rapidly rising ferritin.
• Splenomegaly or hepatosplenomegaly.
• Abnormal liver function tests, jaundice or acute liver injury.
• Coagulopathy, low fibrinogen or bleeding tendency.
• Hypertriglyceridaemia.
• Neurological features such as confusion, seizures or reduced consciousness.
• Clinical picture resembling severe sepsis, but with poor response to antibiotics.

🩺 Clinical Features

• Fever, rigors, malaise and weight loss.
• Splenomegaly and/or hepatomegaly.
• Lymphadenopathy.
• Rash, especially with inflammatory or viral triggers.
• Jaundice, hepatitis-like picture or liver failure.
• Respiratory failure or ARDS-like presentation.
• Renal impairment.
• Neurological involvement: headache, confusion, seizures, meningism or reduced consciousness.
• Bleeding or bruising due to thrombocytopenia and coagulopathy.

🧪 Initial Investigations

• FBC and blood film — cytopenias, abnormal cells, malignancy clues.
• U&Es, LFTs, bone profile, glucose — assess organ dysfunction.
• CRP and ESR — ESR may be low if fibrinogen is depleted.
• Ferritin — often markedly elevated.
• Clotting screen and fibrinogen — look for DIC-like coagulopathy and hypofibrinogenaemia.
• Fasting triglycerides — may be elevated.
• LDH — often elevated due to tissue injury and cell turnover.
• Blood cultures, urine culture and chest imaging — assess for infection.
• Viral testing — EBV, CMV, HIV, hepatitis viruses and respiratory viruses depending on context.
• Autoimmune screen — ANA, ENA, dsDNA, complements and other tests if clinically indicated.
• CT chest/abdomen/pelvis — assess for malignancy, infection, lymphadenopathy or organomegaly.
• Bone marrow aspirate/trephine — assess for malignancy, infection and haemophagocytosis.

📊 HLH-2004 Diagnostic Criteria

HLH can be diagnosed if there is a compatible molecular diagnosis, or if 5 out of 8 HLH-2004 criteria are fulfilled. In adults, these criteria are helpful but should not replace clinical judgement — treatment may be needed before all results are available.

🧠 Important Diagnostic Pearls

• A ferritin of ≥500 micrograms/L is part of the formal criteria, but adult HLH often has ferritin in the thousands or tens of thousands.
• Normal or only mildly raised ferritin makes HLH less likely, but interpretation depends on timing and clinical context.
• Haemophagocytosis on bone marrow supports the diagnosis but is not perfectly sensitive or specific.
• Do not wait for soluble CD25 or NK-cell function results if the patient is critically unwell and HLH is strongly suspected.
• HLH and sepsis can coexist — infection may be both a mimic and a trigger.

🧮 HScore

• The HScore is often used in adults to estimate the probability of reactive HLH.
• It includes temperature, organomegaly, cytopenias, ferritin, triglycerides, fibrinogen, AST, immunosuppression and bone marrow findings.
• It is useful for structured thinking but should not delay urgent specialist treatment.

🧯 Immediate Management Principles

🚨 HLH is a medical emergency. Management should involve urgent senior input from haematology, and often rheumatology, infectious diseases, microbiology, oncology and intensive care. The key priorities are to control the cytokine storm, support failing organs and treat the underlying trigger.

• Admit urgently; many patients require HDU or ICU care.
• Send baseline investigations before treatment if this does not delay care.
• Treat possible sepsis aggressively while also investigating HLH.
• Discuss early with haematology if ferritin is markedly raised with cytopenias and organ dysfunction.
• Search actively for triggers: EBV, CMV, HIV, lymphoma, autoimmune disease, TB and other infections.
• Provide supportive care: blood products, fibrinogen replacement, renal support, ventilation and organ support as needed.

💊 Specific Treatment Options

• Corticosteroids are commonly used to suppress immune activation.
• Anakinra, an IL-1 receptor antagonist, may be used particularly in inflammatory / macrophage activation syndrome phenotypes and is commissioned by NHS England for HLH within defined criteria.
• Etoposide-based regimens may be required, especially in severe EBV-HLH, familial HLH or malignancy-associated HLH.
• Rituximab may be considered in EBV-driven disease where B-cell depletion is appropriate.
• Antimicrobials should be targeted to suspected or confirmed infection.
• Chemotherapy or lymphoma-directed treatment may be required if malignancy is the trigger.
• Stem cell transplantation may be required in familial, relapsed or refractory HLH.

🦠 Infection-Associated HLH

• EBV is a classic trigger and may cause severe HLH.
• CMV, HIV, tuberculosis and leishmaniasis are important causes to consider.
• Always involve microbiology / infectious diseases early.
• Immunosuppressive treatment may be lifesaving, but infection control remains essential.

🧬 Malignancy-Associated HLH

• Most often associated with haematological malignancy, especially lymphoma.
• Can present before the malignancy has been diagnosed.
• Clues include lymphadenopathy, B symptoms, very high LDH, abnormal blood film or unexplained organomegaly.
• Requires urgent haematology / oncology input because definitive treatment often requires malignancy-directed therapy.

🌡️ Macrophage Activation Syndrome

• Macrophage activation syndrome is an HLH-like syndrome occurring in rheumatological disease.
• It is classically associated with systemic juvenile idiopathic arthritis and adult-onset Still’s disease.
• It can also occur with SLE and other inflammatory conditions.
• Clues include fever, rash, falling blood counts, hepatitis, low fibrinogen and very high ferritin.
• Rheumatology input is essential; treatment may include corticosteroids, anakinra or other immunomodulatory therapy.

🧠 CNS HLH

• HLH can affect the central nervous system.
• Features include seizures, confusion, meningism, cranial nerve signs, reduced consciousness or focal neurology.
• Consider MRI brain and lumbar puncture after senior review and if safe.
• CNS involvement often indicates severe disease and requires specialist management.

📉 Monitoring

• Temperature, haemodynamics, fluid balance and organ support needs.
• Daily FBC, U&Es, LFTs, clotting, fibrinogen and ferritin in acute severe disease.
• Triglycerides and inflammatory markers as clinically indicated.
• Monitor for treatment toxicity, infection, cytopenias, renal injury and hepatic injury.
• Assess response by clinical improvement, falling fever burden, improving cytopenias and falling ferritin.

⚠️ Differentials

• Sepsis or septic shock.
• Disseminated intravascular coagulation.
• Acute leukaemia or lymphoma.
• Severe viral infection.
• Adult-onset Still’s disease.
• Systemic lupus erythematosus flare.
• Catastrophic antiphospholipid syndrome.
• Drug reaction with eosinophilia and systemic symptoms.
• Acute liver failure.

🎓 Exam Pearls

• HLH = persistent fever + cytopenias + organomegaly + very high ferritin + coagulopathy.
• Think HLH when “sepsis” is not behaving like sepsis.
• Ferritin can be dramatically high, often much higher than in routine infection.
• Low fibrinogen is a useful clue because many inflammatory states raise fibrinogen.
• Bone marrow haemophagocytosis is helpful but not required to start treatment if suspicion is high.
• Adult HLH is usually secondary — always search for infection, malignancy and autoimmune disease.

🧠 Simple Memory Aid

HLH = Hot, Large spleen, Low cells, High ferritin
🔥 Hot = fever
🫀 Large spleen = splenomegaly
🩸 Low cells = cytopenias
📈 High ferritin = hyperinflammation

✅ Key Takeaway

HLH is a rare but rapidly fatal hyperinflammatory syndrome. Consider it in any severely unwell patient with persistent fever, cytopenias, organ dysfunction, low fibrinogen and very high ferritin, particularly when sepsis treatment is not working. Early recognition, urgent specialist input and prompt treatment of both inflammation and the underlying trigger can be lifesaving.