What is the appropriate work‑up for low‑grade lymphadenitis (persistent mildly inflamed lymph nodes)?

Work-up of Low-Grade Adenitis (Persistent Mildly Inflamed Lymph Nodes)

For persistent low-grade lymphadenopathy lasting ≥4 weeks, proceed directly to definitive diagnostic workup with imaging and laboratory studies, as partial resolution may represent infection overlying malignancy, and avoid empiric antibiotics or corticosteroids which can mask underlying diagnoses. 1, 2, 3

Initial Risk Stratification

Determine if lymphadenopathy is localized or generalized, as this fundamentally changes your differential diagnosis and workup approach 1, 2:

• Localized lymphadenopathy (single region): Consider infectious focus in drainage area, mycobacterial disease, or regional malignancy 1, 4, 2
• Generalized lymphadenopathy (≥2 regions): Strongly suggests systemic disease—hematologic malignancy, HIV, autoimmune disorders, or disseminated infection 4, 2, 3

High-Risk Features Requiring Urgent Workup

Immediately escalate evaluation if any of these features are present 1, 2, 3:

• Node characteristics: Size >2 cm, hard/firm consistency, fixed/matted to surrounding structures, supraclavicular or epitrochlear location (>5 mm) 1, 2, 3
• Systemic symptoms: Fever, drenching night sweats, unexplained weight loss >10% body weight 5, 2, 3
• Demographics: Age >40 years, male sex, white race 3
• Duration: Persistence >4 weeks without significant fluctuation 1, 2

Mandatory Laboratory and Imaging Studies

For persistent low-grade adenitis, obtain 2, 3:

• Complete blood count with differential to evaluate for hematologic malignancy or systemic infection 2
• Erythrocyte sedimentation rate (ESR) and C-reactive protein to assess inflammatory burden 5, 2
• Tuberculosis testing (tuberculin skin test or interferon-gamma release assay), especially if unilateral cervical adenopathy or risk factors present 1, 6, 4
• Contrast-enhanced CT of the involved region to characterize node architecture and identify additional pathology 5, 2
• HIV and hepatitis B/C testing if risk factors present or unusual disease presentation 5, 4

Age-Specific Considerations

In children (especially ages 1-5 years) 1, 4:

• Nontuberculous mycobacterial (NTM) lymphadenitis is the leading consideration for unilateral, non-tender cervical adenopathy that develops insidiously without systemic symptoms 1, 4
• MAC causes approximately 80% of culture-proven NTM cases in this age group 1, 4
• Do NOT use empiric antibiotics in the absence of acute bacterial infection signs (rapid onset, fever, tenderness, overlying erythema) 1

In adults 6, 4:

• Tuberculous lymphadenitis accounts for >90% of culture-proven mycobacterial lymphadenitis 6, 4
• Lymphoma and other malignancies must be excluded, particularly with supraclavicular or posterior cervical involvement 4, 3

Tissue Diagnosis Strategy

When lymphadenopathy persists >4 weeks or high-risk features are present, proceed to biopsy 1, 7, 2, 3:

• Excisional lymph node biopsy is preferred for suspected lymphoma or mycobacterial disease, as it provides optimal tissue architecture for diagnosis 5, 6
• Core needle biopsy may be adequate if diagnostic tissue can be obtained 5
• Fine-needle aspiration (FNA) is insufficient as a sole diagnostic method except when combined with immunohistochemistry and interpreted by expert hematopathologist 5

Critical Pitfall to Avoid

Never perform incisional biopsy or drainage alone for suspected mycobacterial lymphadenitis, as this frequently leads to sinus tract formation and chronic drainage—complete excision is required for NTM disease 6, 4

Follow-Up Protocol for Initially Benign-Appearing Nodes

If you initially observe without biopsy 1:

• Schedule follow-up within 2 weeks to evaluate for resolution, progression, or persistence 1
• If the node has not completely resolved, proceed immediately to definitive workup, as partial resolution may represent infection in underlying malignancy 1
• If complete resolution occurs, schedule one additional follow-up in 2-4 weeks to monitor for recurrence 1

What NOT to Do

Avoid corticosteroids in unexplained lymphadenopathy, as they mask histologic diagnosis of lymphoma or malignancy 2, 3

Do not use empiric antibiotics unless acute bacterial lymphadenitis with systemic symptoms is clearly present (rapid onset, fever, tenderness, erythema) 1, 3

Do not delay biopsy beyond 4 weeks in persistent lymphadenopathy, especially in adults where malignancy risk is substantial 1, 7, 2