How to differentiate between infection and disease flare in a lupus patient presenting with fever?

Differentiating Infection from Disease Flare in Febrile Lupus Patients

In a lupus patient presenting with fever, laboratory markers including elevated C-reactive protein (CRP), increased total leukocyte count (TLC), and normal complement levels strongly suggest infection, while elevated anti-dsDNA antibodies and low complement levels point to disease flare. 1

Diagnostic Algorithm for Fever in Lupus

Step 1: Initial Laboratory Evaluation

• Complete blood count with differential
• C-reactive protein (CRP)
• Erythrocyte sedimentation rate (ESR)
• Complement levels (C3, C4)
• Anti-dsDNA antibodies
• Urinalysis
• Blood cultures (if infection suspected)
• Cerebrospinal fluid examination (if CNS symptoms present)

Step 2: Evaluate Key Differentiating Features

Features Suggesting Infection:

• High CRP levels
• Elevated total leukocyte count
• Increased neutrophil-to-lymphocyte ratio (NLR)
• Normal complement levels
• Normal anti-dsDNA antibodies
• Shaking chills
• Specific site of infection (respiratory, urinary tract, skin)
• Short duration of fever (acute onset)

Features Suggesting Disease Flare:

• Low complement levels (C3, C4)
• Elevated anti-dsDNA antibodies
• High SLEDAI-2K score
• Multiple organ system involvement
• Longer duration of fever
• Relatively lower CRP (compared to infection)

Step 3: Apply Validated Prediction Models

A composite score using age, total leukocyte count, and CRP has demonstrated good discrimination between infection and flare with an AUC of 0.88 in the derivation cohort and 0.83 in the validation cohort 1. Another validated model using duration of fever, CRP, and anti-dsDNA antibody levels achieved an AUC of 0.92 in distinguishing between flare and infection 2.

Management Considerations

If Infection Suspected:

• Obtain appropriate cultures before starting antibiotics
• Initiate empiric antibiotics targeting common sites (respiratory tract infections account for 62.6% of infections in lupus patients) 3
• Consider adjusting immunosuppressive therapy temporarily
• Monitor response to antimicrobial therapy

If Disease Flare Suspected:

• Increase glucocorticoid dose (prednisone ≤100 mg/day suppresses SLE fever in 80.6% of patients, usually within 1-5 days) 3
• Adjust disease-modifying therapy as needed
• Monitor response to immunosuppressive therapy

Special Considerations

Concurrent Infection and Flare

• In approximately 8-10% of cases, both infection and disease flare may coexist 3
• These cases require careful management with both antimicrobial and immunosuppressive therapy
• Consider repeat kidney biopsy if lupus nephritis flare is suspected but diagnosis remains uncertain 4

High-Risk Scenarios

• Patients on azathioprine have increased risk of infection-related fever 3
• Severe lupus encephalopathy or hemophagocytic syndrome may present with steroid-resistant fever 3
• Bacteremia occurs in nearly half of infectious episodes and carries a high mortality rate 5

Pitfalls to Avoid

• Relying solely on ESR for differentiation (elevated in both conditions)
• Assuming fever must be from either infection or flare (can be both)
• Delaying empiric treatment while awaiting complete diagnostic workup in severely ill patients
• Overlooking the possibility of malignancy as a cause of fever (rare but reported) 3

By systematically evaluating laboratory markers and clinical features, clinicians can effectively differentiate between infection and disease flare in febrile lupus patients, leading to appropriate treatment decisions and improved outcomes.