Why does an early autoimmune condition (e.g., early systemic lupus erythematosus, adult‑onset Still’s disease, or drug‑induced immune reaction) cause fever, cytopenias, and high ferritin but not meet the full haemophagocytic lymphohistiocytosis (HLH) diagnostic criteria?

Why Early Autoimmune Processes Present with HLH-like Features Without Meeting Full Diagnostic Criteria

The Core Pathophysiologic Explanation

Early autoimmune conditions like systemic lupus erythematosus (SLE), adult-onset Still's disease, or drug-induced immune reactions trigger a hyperinflammatory cascade that produces fever, cytopenias, and hyperferritinemia through cytokine-mediated mechanisms, but they typically lack the extreme degree of immune dysregulation, specific cellular dysfunction (particularly NK cell impairment), and the characteristic hemophagocytosis required to fulfill 5 of 8 HLH-2004 criteria. 1

The fundamental distinction lies in the intensity and completeness of the immune activation cascade. While autoimmune diseases generate significant inflammation with elevated cytokines, they rarely produce the catastrophic, uncontrolled cytokine storm that defines true HLH. 1

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Specific Criteria That Are Often Missing in Early Autoimmune Disease

1. Ferritin Levels: The Magnitude Matters

• While autoimmune conditions commonly produce hyperferritinemia (often 1,000-5,000 μg/L), true HLH typically generates ferritin levels of 7,000-10,000 μg/L or higher, with levels >10,000 μg/L being >90% sensitive and specific for HLH in children and highly suggestive in adults 1
• A ferritin cutoff of >6,000 μg/L is significantly associated with HLH diagnosis and correlates with hemophagocytosis on bone marrow examination and increased mortality 2
• Early autoimmune processes rarely reach these extreme ferritin thresholds 1

2. NK Cell Activity: A Critical Distinguishing Feature

• Low or absent NK cell activity is a specific HLH criterion that is typically normal in early autoimmune disease 1
• This reflects the fundamental cytotoxic dysfunction in HLH that is not present in most autoimmune conditions 1

3. Soluble CD25 (sIL-2 Receptor) Elevation

• HLH requires sCD25 ≥2,400 U/mL, which reflects extreme T-cell activation 1
• Autoimmune diseases may elevate sCD25 modestly, but rarely to this threshold 1
• sCD25 has an area under the curve of 0.90 for diagnosing adult HLH, superior to ferritin (AUC 0.78) 1

4. Hypertriglyceridemia and Hypofibrinogenemia

• HLH requires fasting triglycerides ≥3.0 mmol/L (≥265 mg/dL) and/or fibrinogen ≤1.5 g/L 1
• Early autoimmune disease may show mild metabolic derangements but typically does not produce the severe hypertriglyceridemia and consumptive hypofibrinogenemia seen in HLH 1
• These metabolic abnormalities reflect the profound macrophage activation and cytokine-driven metabolic dysregulation specific to HLH 1

5. Hemophagocytosis: Neither Sensitive Nor Specific

• Hemophagocytosis is present in only 51-60% of confirmed HLH cases at initial presentation 1, 3
• Hemophagocytosis is neither sensitive nor specific and may be absent on initial bone marrow examination; serial aspirates over time may be required 4, 5
• Importantly, hemophagocytosis can occur in autoimmune disease, severe infection, and other inflammatory states without meeting HLH criteria 1

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The Diagnostic Challenge: Overlapping Features

Common Overlapping Manifestations

The following features are present in both early autoimmune disease and HLH, creating diagnostic confusion:

• Fever >38.5°C (present in >90% of HLH but also universal in active autoimmune disease) 1, 4
• Cytopenias affecting ≥2 lineages (common in both SLE and HLH) 1, 6, 7
• Splenomegaly (present in both conditions) 1, 4
• Elevated liver enzymes (seen in both autoimmune hepatitis and HLH) 1, 4

The Critical Distinction: Degree and Progression

The European Hematology Association emphasizes that clinicians must assess whether the combination, extent, and progression of clinical and laboratory abnormalities are unusual, unexpected, and otherwise unexplained by the autoimmune disease alone. 1, 4

Key questions to ask:

• Is the fever unremitting and refractory to disease-modifying therapy? 5
• Are cytopenias rapidly progressive despite treatment? 4, 5
• Is ferritin rapidly rising to extreme levels (>5,000-10,000 μg/L)? 5, 2
• Is there multiorgan dysfunction disproportionate to the autoimmune disease activity? 5

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When Autoimmune Disease Evolves Into True HLH (Macrophage Activation Syndrome)

The Spectrum Concept

Autoimmune-associated HLH (also called macrophage activation syndrome or MAS) represents a distinct clinical entity where the underlying autoimmune disease triggers a secondary HLH syndrome. 1, 5

• SLE-associated HLH is rare but potentially fatal, often occurring in the context of disease flare and rarely at initial diagnosis 6, 7
• Adult-onset Still's disease is a well-recognized trigger for MAS/HLH 1, 5
• The treatment of autoimmune-associated HLH may differ from other forms of secondary HLH 1

Diagnostic Approach in This Gray Zone

When an autoimmune patient presents with HLH-like features but does not meet full criteria, the HScore can provide a probability-based assessment:

• HScore >169 indicates >93% probability of HLH 1
• HScore 90-168 indicates 75-93% probability 1
• The HScore incorporates underlying immunosuppression, temperature, organomegaly, number of cytopenias, ferritin level, triglycerides, fibrinogen, AST, and hemophagocytosis 1

Clinical judgment is paramount: HLH-directed therapy may be initiated even when 5 criteria are not fulfilled if clinical suspicion is high. 1, 4

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Practical Clinical Algorithm

Step 1: Identify Red Flags for Evolving HLH

• Ferritin rapidly rising to >5,000 μg/L (and especially >10,000 μg/L) 1, 5, 2
• Progressive cytopenias despite appropriate autoimmune disease treatment 4, 5
• Unremitting fever refractory to disease-modifying therapy 5
• Development of multiorgan dysfunction (hepatitis, coagulopathy, neurologic symptoms) 5

Step 2: Complete HLH Diagnostic Workup

• Obtain all HLH-2004 parameters: NK cell activity, sCD25, fasting triglycerides, fibrinogen 1
• Perform bone marrow aspiration to assess for hemophagocytosis (but do not delay treatment if coagulopathy is present) 4, 5
• Calculate HScore to quantify probability of HLH 1

Step 3: Assess for Triggers

• Screen for occult malignancy (particularly lymphoma in adults) with CT chest/abdomen/pelvis, consider PET scan 1
• Comprehensive infectious workup including EBV, CMV, HIV, fungal infections 1, 8
• Review medication history for drug-induced triggers 1

Step 4: Treatment Decision

If HScore >169 or ≥5 HLH-2004 criteria are met:

• Initiate high-dose corticosteroids (methylprednisolone 1 g/day IV for 3-5 days) immediately 5
• Simultaneously treat the underlying autoimmune disease with disease-modifying therapy 5
• Consider adding IVIG in severe cases 8

If HScore 90-168 or 3-4 criteria met with high clinical suspicion:

• Do not delay empirical HLH treatment while awaiting all diagnostic criteria 4, 5
• Monitor ferritin, platelets, and clinical status every 12 hours 1, 5
• Escalate to HLH-directed therapy if progression occurs 5

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Critical Pitfalls to Avoid

1. Waiting for All 5 Criteria Before Treating

Delayed diagnosis and treatment significantly increase mortality; empirical treatment should not be delayed while waiting for all HLH-2004 criteria to be met if clinical suspicion is high. 4, 5

2. Over-relying on Hemophagocytosis

Do not rule out HLH based solely on absence of hemophagocytosis, as it may be absent on initial bone marrow examination in up to 49% of cases. 4, 3

3. Ignoring the Ferritin Trajectory

Ferritin increases rapidly in active HLH but normalizes slowly following resolution; monitor the rate of rise, not just the absolute value. 1, 5

4. Attributing All Findings to the Autoimmune Disease

In the context of malignancy or autoimmune disease, several HLH characteristics may be present and caused by HLH and/or by the underlying condition; integration of clinical features is required. 1

5. Missing Coexisting Infections

Viral infections (particularly EBV and CMV) commonly act as co-triggers in autoimmune-associated HLH; comprehensive infectious workup is mandatory. 1, 8, 3

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Prognostic Considerations

Factors associated with higher mortality in HLH include:

• Shock at ICU admission 5
• Platelet count <30 × 10⁹/L 5
• Malignancy-associated HLH (particularly T/NK-cell lymphomas) 5, 3
• Presence of edema and hyperbilirubinemia 3
• Coexisting viral infection 3

Four-year overall survival in adult HLH is only 17.8%, emphasizing the critical importance of early recognition and aggressive treatment. 3