What are the possible causes of leukopenia with relative lymphocytosis and neutropenia presenting as macrophage activation syndrome, accompanied by anemia, thrombocytopenia, and extreme hyperferritinemia?

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Underlying Causes of MAS with Severe Leukopenia and Extreme Hyperferritinemia

In a patient presenting with MAS (ferritin 27,000 ng/mL), leukopenia (1,400), relative lymphocytosis (65%), neutropenia (25%), anemia (Hb 8), and thrombocytopenia (platelets 80,000), you must immediately pursue three primary triggers: infections (particularly EBV and CMV), hematologic malignancies (especially T-cell/NK-cell lymphomas), and underlying autoimmune diseases (Still's disease, SLE, or vasculitis). 1

Primary Diagnostic Considerations

1. Infection-Triggered Secondary HLH

Infections are the most prevalent triggers of HLH in adults 1. The relative lymphocytosis with neutropenia pattern is particularly concerning for:

  • Viral infections - EBV and CMV are the most common culprits 2
  • Other viral triggers - SARS-CoV-2, HIV, parvovirus B19
  • Severe bacterial or fungal sepsis (though less likely with this differential pattern)

The extreme hyperferritinemia (27,000 ng/mL) strongly supports HLH/MAS, as ferritin >10,000 mg/L is >90% sensitive and specific for HLH 1.

2. Malignancy-Associated HLH

In adults, particularly with increasing age, malignancies are a major cause of HLH 1. The distribution is critical:

  • T-cell or NK-cell lymphomas (35% of malignancy-associated HLH) 1
  • B-cell lymphomas (32%) 1
  • Leukemias (6%) 1
  • Hodgkin lymphoma (6%) 1

Critical pitfall: The leukopenia and cytopenias may mask an underlying hematologic malignancy. The lymphocyte predominance could represent a clonal lymphoproliferative disorder rather than reactive lymphocytosis.

3. Autoimmune/Autoinflammatory Disease (MAS-HLH)

The term MAS should be restricted to HLH arising from systemic autoimmune conditions 1:

  • Adult-onset Still's disease (AOSD) - most common cause of MAS in adults 3, 4
  • Systemic lupus erythematosus (SLE) 5
  • Systemic vasculitis
  • Other rheumatologic conditions

These patients may present with MAS as the initial manifestation before the underlying autoimmune disease is recognized 5, 4.

Algorithmic Diagnostic Approach

Immediate Workup Required:

Infectious evaluation:

  • EBV PCR, EBV serology (VCA-IgM, EBNA)
  • CMV PCR and serology
  • HIV testing
  • Blood cultures (bacterial, fungal)
  • SARS-CoV-2 testing
  • Consider hepatitis panel, parvovirus B19

Malignancy screening:

  • Peripheral blood flow cytometry for lymphoproliferative disorders
  • Bone marrow aspiration and biopsy with flow cytometry
  • CT chest/abdomen/pelvis for lymphadenopathy and organomegaly
  • LDH, uric acid levels
  • Do not delay bone marrow examination - it serves dual purpose of identifying hemophagocytosis AND detecting occult malignancy 1, 2

Autoimmune workup:

  • ANA, anti-dsDNA, anti-Smith antibodies (for SLE)
  • Rheumatoid factor, anti-CCP
  • Complement levels (C3, C4)
  • Consider skin biopsy if rash present (salmon-pink rash suggests Still's disease)

HLH-specific parameters:

  • Soluble IL-2 receptor (sCD25) - should be ≥2,400 U/mL 1
  • Triglycerides (≥265 mg/dL) 1
  • Fibrinogen (≤1.5 g/L) 1
  • NK cell activity testing
  • Consider genetic testing for HLH-associated genes if young adult or family history

Critical Management Principle

The search for the underlying trigger must continue despite initiating HLH treatment 1. This is a strong consensus recommendation because:

  1. Treatment differs based on the trigger (MAS-HLH may require different immunosuppression than infection-triggered HLH)
  2. Malignancies can be occult and require persistent investigation
  3. Mortality is significantly higher when the underlying cause is not addressed

Common Pitfalls to Avoid:

  • Do not assume infection alone - In adults, malignancy-associated HLH has cumulative incidence rates of 1-9% in hematologic malignancies 1
  • Do not wait for all 5 HLH-2004 criteria - Clinical judgment may warrant treatment initiation even without meeting full criteria 1
  • Do not overlook autoimmune disease - MAS can be the presenting feature of previously undiagnosed SLE or Still's disease 5, 4
  • Do not perform single bone marrow examination - Serial aspirates may be needed if initial biopsy is non-diagnostic 1

Specific Laboratory Pattern Interpretation

Your patient's specific findings warrant emphasis:

  • Leukopenia with lymphocyte predominance suggests either viral infection (EBV/CMV) or lymphoproliferative disorder
  • Neutropenia (25%) meets HLH-2004 criteria (<1.0 × 10⁹/L) 1
  • Ferritin 27,000 ng/mL is in the highly specific range for HLH (>10,000 mg/L) 1
  • Bicytopenia (anemia + thrombocytopenia) meets HLH criteria (≥2 lineages affected) 1

The combination of extreme hyperferritinemia with this cytopenia pattern and relative lymphocytosis creates high suspicion for either EBV-driven HLH or T-cell lymphoma-associated HLH. Both require urgent identification as they have different treatment implications and significantly impact mortality.

References

3
Research

Macrophage Activation Syndrome.

Indian journal of pediatrics, 2016

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