1. Active SLE-associated MAS-HLH
2. Infection-triggered HLH, especially EBV, CMV, tuberculosis, malaria/leishmaniasis where endemic, bacterial sepsis, and fungal infection
3. Infective endocarditis (IE), which must be actively excluded because rheumatic valvular disease plus fever is a high-risk setting
4. Malignancy-associated HLH, especially lymphoma or leukemia
5. Other causes of cytopenia: SLE immune cytopenias/Evans syndrome, thrombotic microangiopathy/TTP, drug toxicity, DIC, marrow infiltration or aplasia

1. Immediate approach: first hours

Stabilize and assess severity

• ABCs, continuous observations, urine output, mental status
• Screen for shock, respiratory failure, encephalopathy, bleeding/DIC, myocarditis, acute heart failure, renal injury, hepatitis, and seizures
• Daily or twice-daily CBC, ferritin, fibrinogen, coagulation profile, liver function, renal function, LDH, and triglycerides if deteriorating
• Transfuse blood components based on clinical status:
  • Red cells for symptomatic/severe anemia
  • Platelets for active bleeding, invasive procedures, or very low counts
  • Cryoprecipitate/fibrinogen replacement if hypofibrinogenemia with bleeding or DIC
• Avoid unnecessary invasive procedures while thrombocytopenic/coagulopathic.

Treat possible sepsis without delay

2. Confirm whether she has active HLH/MAS

HLH-2004 criteria

• Fever
• Splenomegaly
• Cytopenia of at least 2 lineages:
  • Hb <9 g/dL
  • Platelets <100 × 10⁹/L
  • Neutrophils <1.0 × 10⁹/L
• Fasting triglycerides ≥265 mg/dL (3 mmol/L) and/or fibrinogen ≤150 mg/dL (1.5 g/L)
• Hemophagocytosis in marrow, spleen, lymph node, or liver
• Low/absent NK-cell activity
• Ferritin ≥500 ng/mL
• Raised soluble IL-2 receptor, sCD25

Essential initial HLH panel

• CBC with differential, reticulocyte count, peripheral smear
• Ferritin, LDH, fasting triglycerides, fibrinogen
• PT/INR, aPTT, D-dimer, liver function including bilirubin/AST/ALT, albumin
• Creatinine, electrolytes, urate, calcium, phosphate, lactate
• CRP and ESR. A relatively low/falling ESR with very high CRP may occur when fibrinogen is consumed.
• Soluble CD25/sIL-2R, NK-cell function if available. Do not await these tests.
• Bone marrow aspirate and trephine biopsy with morphology, flow cytometry, cytogenetics, cultures/stains, and evaluation for leukemia/lymphoma/infection.

3. Establish the precipitating cause in parallel

A. Evaluate for active SLE and SLE-MAS

• ANA titre/pattern, anti-dsDNA, anti-Sm if not already documented
• C3, C4, CH50
• Urinalysis, urine protein-creatinine ratio, urine microscopy
• Direct antiglobulin test, bilirubin, haptoglobin, reticulocytes for autoimmune hemolysis
• Antiphospholipid antibodies when clinically indicated
• Assess for rash, oral ulcers, arthritis, serositis, nephritis, CNS lupus, autoimmune hemolysis, immune thrombocytopenia.

B. Treat rheumatic valvular disease plus fever as possible infective endocarditis

• Draw 3 sets of blood cultures from separate venepuncture sites before antibiotics, if feasible.
• Perform urgent transthoracic echocardiography (TTE).
• If TTE is negative/nondiagnostic but suspicion persists, or if images are poor/valvular pathology is complex, perform transoesophageal echocardiography (TEE).
• Look for new/changing murmur, heart failure, embolic phenomena, splenomegaly, microscopic hematuria, neurologic events, Janeway lesions, Roth spots, and conduction abnormalities.
• Repeat cultures and echocardiography when clinically indicated.

C. Infection work-up

• Blood cultures, urine culture, chest imaging, sputum studies where indicated
• EBV PCR, CMV PCR, HIV, hepatitis B/C
• Respiratory viral testing as appropriate
• Malaria smear/rapid antigen if exposure risk
• TB testing and targeted imaging/samples if risk
• Visceral leishmaniasis testing in endemic exposure with fever, splenomegaly, cytopenias
• Fungal studies if immunocompromised or prolonged neutropenia
• Consider parvovirus B19 and dengue depending on syndrome/location.

D. Malignancy evaluation

• Peripheral smear reviewed by hematopathology
• Bone marrow flow cytometry and biopsy
• CT chest/abdomen/pelvis, or PET-CT once stable, for occult lymphoma
• Biopsy any accessible lymph node, liver lesion, or mass
• Excisional lymph-node biopsy is preferred when lymphoma is suspected.

4. Differential diagnosis to actively exclude

5. Disease-directed treatment

If clinical HLH/MAS is likely and she is ill

1. Control of hyperinflammation
2. Treatment of the trigger
3. Organ support and management of complications

First-line in probable SLE-associated MAS-HLH

• High-dose IV methylprednisolone pulse therapy is generally initial treatment for severe SLE-MAS.
• Then transition to a high-dose oral glucocorticoid regimen with reassessment of ferritin, counts, fibrinogen, transaminases, fever, and organ function.
• Treat a confirmed trigger simultaneously, especially infection.

Escalation if severe, progressive, refractory, or trigger is malignancy/EBV

• Etoposide plus dexamethasone-based HLH therapy, particularly for severe HLH, EBV-HLH, malignancy-associated HLH, CNS disease, or failure to respond to steroids
• Cyclosporine may be used in rheumatic MAS in selected cases
• IVIG, especially where infection coexists or immunosuppression needs caution
• Anakinra, an IL-1 blocker, is increasingly used for secondary HLH/MAS, particularly in rheumatic disease or when concern exists about etoposide toxicity
• Ruxolitinib or other cytokine-directed approaches only in specialist settings
• Rituximab may have a role in EBV-driven B-cell disease or selected SLE manifestations
• Treat underlying lymphoma urgently if malignancy-associated HLH is confirmed.

Infection and IE caveat

• Do not withhold antibiotics while evaluating HLH.
• Do not assume fever is lupus flare.
• Immunosuppression may still be needed for life-threatening HLH, but the decision should be made jointly with infectious disease, rheumatology, and hematology, with close microbiologic surveillance.

6. Monitoring response

• Temperature and hemodynamics
• CBC and differential
• Ferritin trend
• Fibrinogen, triglycerides, PT/aPTT/D-dimer
• AST/ALT, bilirubin, creatinine, LDH
• Neurologic status
• Evidence of bleeding, thrombosis, liver failure, heart failure, or new infection
• Serial blood cultures if bacteremia/IE is suspected or documented

Practical working impression

Secondary HLH/MAS, potentially precipitated by active SLE, infection, or both, with infective endocarditis requiring urgent exclusion because of underlying rheumatic valvular heart disease.

1. Resuscitate and culture.
2. Obtain urgent TTE and proceed to TEE if necessary.
3. Send HLH/MAS and SLE activity panels, marrow studies, infection studies, and malignancy screen.
4. Start antimicrobials promptly if septic/IE is possible.
5. Start high-dose corticosteroid treatment promptly if the HLH/MAS phenotype is strong or organ dysfunction is evolving, while involving hematology/rheumatology/ID to decide on anakinra, cyclosporine, or etoposide escalation.