In a 35-year-old hypertensive man with diffuse alveolar hemorrhage and rapidly progressive glomerulonephritis due to anti‑glomerular basement membrane disease, can fever occur without an infection?

Can Fever Present in Anti-GBM Disease Without Infection?

Yes, fever can occur in anti-GBM disease without infection, though the majority of febrile patients (approximately 79%) do have concurrent infections. 1

Fever as a Disease Manifestation

Fever is a common presenting symptom in anti-GBM disease, occurring in approximately 67% of patients prior to admission or within 48 hours of hospitalization. 1 This represents a substantial proportion of the disease presentation and should not automatically be attributed to infection alone.

Fever Without Infection

Among febrile patients with anti-GBM disease, approximately 21% present with fever in the absence of documented infection. 1 This suggests that fever can be a direct manifestation of the underlying autoimmune inflammatory process itself, likely related to:

• Systemic inflammatory response from the autoimmune vasculitis
• Cytokine release associated with active glomerulonephritis and alveolar hemorrhage
• Tissue injury from the rapidly progressive nature of the disease

Clinical Significance of Fever

Patients presenting with fever demonstrate more severe disease activity and worse outcomes. 1 Specifically, febrile patients show:

• Higher serum anti-GBM antibody levels (154.9 ± 58.4 vs. 106.0 ± 63.2 IU/mL) 1
• More severe renal dysfunction with higher serum creatinine (733.4 ± 402.5 vs. 580.6 ± 368.1 μmol/L) 1
• More aggressive histologic disease with higher percentage of crescents (87.0 ± 15.6% vs. 67.4 ± 37.6%) 1
• Higher progression to ESRD (80.9% vs. 60.9%) 1

Infection Considerations

While fever without infection can occur, infection remains the predominant cause of fever in anti-GBM disease, affecting 66% of all patients (93/140). 1 The most common sites include:

• Pulmonary infections (47.3% of infections) 1
• Upper respiratory tract infections (31.2% of infections) 1

Common pathogens identified include Candida albicans, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. 1

Clinical Approach

Before initiating cyclophosphamide, infection must be sufficiently ruled out, though corticosteroids and plasma exchange can begin empirically when anti-GBM disease is suspected. 2 This is critical because:

• The aggressive immunosuppression required for anti-GBM disease carries substantial infection risk 2
• Cyclophosphamide administration should ideally wait until disease confirmation and adequate infection workup 2
• However, treatment should not be delayed if anti-GBM disease is highly suspected, as early intervention is crucial for renal survival 2

ANCA Co-positivity

Approximately 16% of febrile anti-GBM patients are also ANCA-positive (specifically MPO-ANCA), which is comparable to non-febrile patients. 1 This "double-positive" status does not explain the fever but does have important treatment implications, as these patients require maintenance immunosuppression similar to ANCA-associated vasculitis. 2

Key Clinical Pitfall

Do not delay treatment while pursuing exhaustive infection workup if anti-GBM disease is strongly suspected. 2 The rapidly progressive nature of anti-GBM disease means that untreated disease causes high morbidity and mortality. 2 Empirical high-dose corticosteroids and plasma exchange should begin immediately, with cyclophosphamide added once infection is reasonably excluded and diagnosis confirmed. 2