Causes of Necrotizing Lymphadenitis
Necrotizing lymphadenitis (Kikuchi-Fujimoto disease) is a rare, benign, self-limited condition of unknown etiology, though evidence strongly suggests a hyperactive immune response to viral infection as the most likely cause. 1, 2, 3
Primary Etiologic Theories
Viral Trigger Hypothesis
- The most supported theory is that necrotizing lymphadenitis represents a hyperactive immune response to viral infection, with several viral agents implicated 3, 4
- Epstein-Barr virus (EBV) has been suggested as a potential trigger based on clinical associations 5, 4
- Herpesvirus type 6 and cytomegalovirus (CMV) have been identified in some cases, with positive CMV serology documented in patients with confirmed disease 4
- Recent case reports suggest possible association with mRNA COVID-19 vaccination, indicating potential post-viral or vaccine-related immune activation 1
Autoimmune Association
- Strong association exists with systemic lupus erythematosus (SLE), with 9% of European patients and 28% of East Asian patients developing concomitant SLE 6
- Cutaneous lupus erythematosus has been documented in association with Kikuchi-Fujimoto disease, suggesting shared immunopathogenic mechanisms 4
- The disease may represent an early manifestation or precursor to autoimmune conditions, warranting long-term follow-up 6
Important Differential Diagnoses to Exclude
Infectious Causes That Mimic Necrotizing Lymphadenitis
- Nontuberculous mycobacterial (NTM) lymphadenitis must be distinguished, as it requires different management - NTM causes 80% of culture-proven mycobacterial lymphadenitis in children, predominantly affecting cervical nodes 7
- Tuberculosis accounts for >90% of mycobacterial lymphadenitis in adults and requires drug therapy plus public health tracking 7
- Tuberculin skin testing should be performed to distinguish tuberculous from NTM lymphadenitis, though children with NTM may show reactions up to 10mm induration 7
Non-Infectious Mimics
- Malignant lymphoma is the most critical differential diagnosis, as Kikuchi-Fujimoto disease is often mistaken for malignancy 1, 2
- Kawasaki disease presents with cervical lymphadenopathy (≥1.5 cm diameter, usually unilateral) but includes additional diagnostic criteria: fever ≥5 days, conjunctival injection, oral changes, rash, and extremity changes 7
Clinical Pitfalls to Avoid
- Do not rely on fine-needle aspiration alone for diagnosis - excisional biopsy is required for definitive histopathological diagnosis showing characteristic histiocytic necrotizing lymphadenitis 8, 1, 2
- Do not assume bacterial infection and treat empirically with antibiotics - this delays proper diagnosis and is inappropriate without signs of acute bacterial infection 8
- The presence of exudative conjunctivitis, exudative pharyngitis, oral ulcerations, or splenomegaly should prompt consideration of alternative diagnoses rather than Kikuchi-Fujimoto disease 7
- Hard, persistent lymphadenopathy (≥1.5 cm for ≥2 weeks) requires prompt biopsy to exclude malignancy, as observation alone is inadequate 8