In a patient with fever, splenomegaly, cytopenias and possible hemophagocytic lymphohistiocytosis, could a connective‑tissue disorder such as systemic lupus erythematosus or malaria be the underlying cause?

Can Connective Tissue Disorders or Malaria Cause HLH with This Presentation?

Yes, both systemic lupus erythematosus and malaria are well-documented triggers of hemophagocytic lymphohistiocytosis and must be actively excluded in any patient presenting with fever, splenomegaly, and cytopenias.

Malaria as the Underlying Cause

Clinical Likelihood and Diagnostic Features

Malaria should be at the top of your differential diagnosis if there is any travel history to endemic areas. The clinical presentation described—fever, splenomegaly, and cytopenias—has extremely high predictive value for malaria in the appropriate epidemiologic context 1.

• Fever has a positive likelihood ratio of 5.1 for malaria diagnosis, and splenomegaly has a likelihood ratio of 6.6-13.6 1
• Thrombocytopenia (<150,000/mL) occurs in 70-79% of malaria cases regardless of Plasmodium species and has a positive likelihood ratio of 5.6-11.0 1
• Any thrombocytopenic patient with platelet count <100,000/mL should be screened for malaria to avoid misdiagnosis 1

Malaria-Associated HLH

Malaria can trigger secondary HLH, though it occurs in only 0.34% of malaria cases 2. However, this may represent significant underdiagnosis, particularly in resource-limited settings 2.

• The median time from malaria symptom onset to hospital admission in malaria-HLH cases is 7 days 2
• Severe complications occur in 36% of malaria-associated HLH cases, including multiorgan failure 2
• The mortality rate for malaria-associated HLH is approximately 5%, which is notably lower than HLH triggered by other infections (e.g., 25% for EBV-associated HLH) 2

Immediate Diagnostic Actions for Malaria

• Obtain thick and thin blood films with Giemsa staining immediately—this remains the gold standard 1
• Order rapid diagnostic tests (RDTs) for Plasmodium antigens if microscopy expertise is limited; sensitivity for P. falciparum >100 parasites/mL approaches that of expert microscopy 1
• Screen all thrombocytopenic samples with platelets <100,000/mL for malaria 1
• Elicit comprehensive travel history including regions visited, duration since return, and time between return and symptom onset 1

Systemic Lupus Erythematosus as the Underlying Cause

SLE-Associated HLH Characteristics

SLE is a well-established trigger of secondary HLH, accounting for 94 of 421 reported cases of HLH in rheumatic diseases 3. This association is critical because the clinical features of SLE flare and HLH overlap substantially, making differentiation challenging but essential for survival 4.

Key Distinguishing Features

Several laboratory parameters can help differentiate SLE-associated HLH from isolated lupus flare:

• Hyperferritinemia with ferritin >5,000-10,000 μg/L strongly suggests HLH rather than lupus flare alone 5, 4
• Hypofibrinogenemia and hypertriglyceridemia are characteristic of HLH but not typical of SLE flare 4
• Decreased or absent NK cell activity by flow cytometry is a hallmark of HLH 4
• ESR is typically decreased in HLH but elevated in SLE flare 4

Diagnostic Workup for SLE

• Check ANA, anti-dsDNA, complement levels (C3, C4), and complete autoimmune serologies 3
• Measure ferritin, triglycerides, fibrinogen, and soluble CD25 to assess for HLH criteria 6, 4
• Perform flow cytometry for NK cell activity if HLH is suspected 4
• Obtain bone marrow aspiration to look for hemophagocytosis and exclude malignancy 6, 5

Critical Management Algorithm

Step 1: Immediate Parallel Workup (Do Not Delay)

Both malaria and SLE can coexist with HLH, and infections can trigger HLH in patients with underlying autoimmune disease 1.

• Send malaria diagnostics (blood films, RDTs) immediately regardless of autoimmune workup 1
• Send comprehensive autoimmune panel including ANA, anti-dsDNA, complements 3
• Measure HLH-2004 criteria parameters: ferritin, triglycerides, fibrinogen, soluble CD25 6, 5
• Obtain bone marrow aspiration for hemophagocytosis and malignancy screening 6, 5

Step 2: Assess HLH Diagnostic Criteria

If the patient meets ≥5 of 8 HLH-2004 criteria (fever, splenomegaly, cytopenias affecting ≥2 lineages, hypertriglyceridemia/hypofibrinogenemia, hemophagocytosis, low NK activity, ferritin ≥500 μg/L, soluble CD25 ≥2,400 U/mL), HLH is confirmed 6, 5.

Step 3: Initiate Treatment Based on Findings

If malaria is confirmed:

• Start antimalarial therapy immediately (artemisinin-based combination therapy for P. falciparum) 1
• If HLH criteria are met and patient continues to deteriorate despite antimicrobial treatment, add high-dose corticosteroids (methylprednisolone 1g/day IV for 3-5 days) 1, 5
• Monitor ferritin, cell counts, triglycerides every 12-24 hours 5

If SLE is confirmed:

• Initiate high-dose corticosteroids immediately (methylprednisolone 1g/day IV for 3-5 days) 5
• Add disease-modifying therapy for SLE (hydroxychloroquine, mycophenolate, or cyclophosphamide depending on organ involvement) 5
• Consider second-line agents (cyclosporine A, anakinra, or tocilizumab) if inadequate response to corticosteroids 1, 5

Step 4: Escalate if Refractory

If patient deteriorates despite initial therapy:

• Add etoposide-based therapy for refractory HLH 1, 5
• Transfer to ICU if shock, platelet count <30,000/μL, or grade ≥2 organ dysfunction develops 5
• Reassess every 12 hours with ferritin, cell counts, organ function, and inflammatory markers 5

Critical Pitfalls to Avoid

• Do not assume fever and cytopenias are solely due to SLE flare without excluding infection—malaria and other infections commonly trigger HLH in autoimmune patients 1
• Do not delay empirical HLH treatment while waiting for all diagnostic criteria if ferritin >10,000 μg/L with progressive cytopenias 5
• Do not overlook geographic exposure history—even patients without recalled tick or mosquito bites can have vector-borne infections 1
• Do not rely solely on presence or absence of hemophagocytosis in bone marrow—it may be absent initially and is neither sensitive nor specific 1, 6
• Do not withhold immunosuppression in confirmed infection-triggered HLH if the patient meets HLH criteria and continues deteriorating despite pathogen-specific therapy 1