In a child‑bearing‑age woman with systemic lupus erythematosus on chronic immunosuppression (e.g., corticosteroids, hydroxychloroquine, azathioprine, mycophenolate mofetil, or belimumab), how can I differentiate a lupus flare from an infection?

Distinguishing SLE Flare from Infection in Immunosuppressed Women

In a febrile woman with SLE on chronic immunosuppression, markedly elevated C-reactive protein (>50 mg/L) strongly suggests infection rather than lupus activity alone and should trigger immediate infection workup before escalating immunosuppression. 1

Clinical Assessment Framework

Fever Evaluation

• Fever with CRP >50 mg/L: This pattern indicates infection rather than pure lupus activity, as SLE typically does not produce significantly elevated CRP unless complicated by serositis or superimposed infection 1, 2
• Fever with normal or mildly elevated CRP: More consistent with lupus flare, particularly when accompanied by other serologic markers of disease activity 3

Critical Respiratory Presentations

Never escalate immunosuppression in a febrile lupus patient with new pulmonary infiltrates without first excluding infection through bronchoscopy with bronchoalveolar lavage—this represents a potentially fatal error. 1

• Pulmonary infiltrates with hypoxemia require infection exclusion before assuming lupus pneumonitis 1
• Common infections in SLE include pneumonia, urinary tract infection, cellulitis, and sepsis with typical bacterial pathogens (Gram-positive and Gram-negative) 2
• Opportunistic infections occur especially with immunosuppressive therapy 2, 4

Laboratory Differentiation Strategy

Markers Favoring Lupus Flare

• Rising anti-dsDNA antibodies: Correlate with disease activity, particularly renal flares 1, 5
• Low complement levels (C3, C4): Indicate active disease and immune complex consumption 1, 6, 5
• Active urine sediment with cellular casts: Suggests active nephritis 1
• Rising proteinuria (urine protein:creatinine ratio): Indicates active kidney involvement 1
• Normal or mildly elevated CRP: Typical of lupus activity without infection 1, 3

Markers Favoring Infection

• CRP >50 mg/L: Strongly suggests bacterial infection 1, 3
• Procalcitonin elevation: Helps distinguish infection from inflammatory processes 5, 3
• Normal complement levels with fever: Less consistent with active lupus 3
• Absence of rising anti-dsDNA: Makes pure lupus flare less likely 5

Emerging Biomarkers

• CD64-Fc receptor expression: Supported by convincing evidence to discriminate between SLE activity and infection 5
• Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1): Potential marker under investigation 5
• Single biomarkers may be insufficient; combination scores incorporating multiple markers represent a better approach 3

Organ-Specific Flare Manifestations

Renal Involvement

• Rising serum creatinine and declining eGFR signal worsening renal function 1
• Hypertension develops or worsens with renal flares 1, 6
• Renal flares occur in up to 45% of lupus nephritis patients 1, 6
• Flare risk increases with low complement or high anti-dsDNA titers 7

Neuropsychiatric Manifestations

• Headache, mood disorders, seizures, and cognitive impairment characterize CNS involvement 1, 6
• Seizures and cerebrovascular events indicate severe organ-threatening disease 1
• Neuropsychiatric symptoms require careful clinical assessment as no specific validated instrument exists 1

Hematologic Changes

• Severe cytopenias (anemia, thrombocytopenia, leukopenia, lymphopenia) indicate active disease 1, 6
• Severe leukopenia and lymphopenia paradoxically increase infection risk while indicating disease activity 1

Mucocutaneous and Musculoskeletal Features

• Lupus-specific skin lesions include malar rash, photosensitive rash, discoid lesions 1, 6
• Polyarthritis affecting multiple joints characterizes mild-to-moderate flares 1
• Serositis (pleuritis, pericarditis) may be mild-to-moderate or severe depending on extent 1

Risk Factors for Infection in SLE

• Severe flares and active renal disease increase infection susceptibility 2, 4
• Moderate or high-dose corticosteroids (>7.5 mg/day prednisone equivalent chronically) 8, 2
• Immunosuppressive agents (azathioprine, mycophenolate mofetil, cyclophosphamide) 2, 4
• Genetic factors including complement deficiencies may predispose certain patients 2

Practical Clinical Algorithm

1. Obtain immediate laboratory panel: Anti-dsDNA, C3, C4, CBC, creatinine, urine protein:creatinine ratio, CRP, procalcitonin 1, 5, 3

2. If CRP >50 mg/L or procalcitonin elevated: Pursue infection workup aggressively with cultures (blood, urine, sputum), imaging, and consider bronchoscopy if pulmonary infiltrates present 1, 3

3. If low complement + rising anti-dsDNA + normal/low CRP: Favor lupus flare and consider immunosuppression escalation 1, 5

4. If clinical picture ambiguous: Both conditions may coexist; treat infection empirically while monitoring lupus serologies closely 2, 4

Common Pitfalls to Avoid

• Assuming fever always represents lupus activity without checking CRP—significantly elevated CRP demands infection exclusion 1, 3
• Escalating immunosuppression before excluding infection in patients with pulmonary infiltrates 1
• Relying on single biomarkers rather than comprehensive clinical and laboratory assessment 3
• Overlooking that infection and flare can coexist simultaneously 2, 4
• Failing to screen for latent infections (tuberculosis, hepatitis B/C, HIV) before initiating or intensifying immunosuppression 8, 2

Special Considerations in Pregnancy

• Lupus flare incidence in pregnancy ranges from 11-28%, higher with low complement or high anti-dsDNA 7
• Hydroxychloroquine should be continued during pregnancy as withdrawal increases flare risk 7
• Active lupus nephritis during pregnancy can be treated with glucocorticoids plus azathioprine and/or calcineurin inhibitors 7
• Mycophenolate must be discontinued or changed to azathioprine if pregnancy occurs 7