What is the management approach for systemic lymphadenopathy in a patient with Human Immunodeficiency Virus (HIV)?

Management of Systemic Lymphadenopathy in HIV Patients

Persistent generalized lymphadenopathy in HIV patients is typically benign and does not require specific treatment, but localized lymphadenopathy or organomegaly warrants immediate evaluation for infection or malignancy. 1

Initial Clinical Assessment

Distinguish between benign persistent generalized lymphadenopathy (PGL) and pathologic lymphadenopathy:

• PGL is common in HIV infection and does not correlate with prognosis or disease progression 1
• Localized lymphadenopathy, hepatomegaly, or splenomegaly may indicate infection or malignancy and requires further evaluation 1
• Assess for constitutional symptoms (fever >37.8°C for ≥2 weeks, night sweats, weight loss) which suggest opportunistic infection or malignancy 1
• Examine for skin lesions (Kaposi sarcoma), oral candidiasis, or hairy leukoplakia which indicate advanced disease 1

Risk Stratification by CD4 Count

CD4 count determines the differential diagnosis and urgency of workup:

• CD4 >500 cells/μL: Usually no clinical immunosuppression; reactive lymphadenopathy most likely 1
• CD4 200-500 cells/μL: Increased risk of HIV-related symptoms; tuberculosis becomes more common 1
• CD4 <200 cells/μL: High risk for opportunistic infections (TB, MAC, fungal) and lymphomas; requires comprehensive evaluation in specialty setting 1
• CD4 <50 cells/μL: Mycobacterium avium complex (MAC) infection most common 2

Mandatory Initial Laboratory Evaluation

All HIV patients with significant lymphadenopathy (>1 cm extrainguinal) require:

• CD4+ T-lymphocyte count (absolute number and percentage) 1
• HIV viral load to assess disease control 3
• Complete blood count and platelet count 1
• Syphilis serology 1
• Tuberculin skin test (PPD) by Mantoux method with anergy panel (Candida, mumps, or tetanus toxoid) 1
• PPD ≥5 mm induration is considered positive in HIV patients and requires TB evaluation 1

Diagnostic Workup for Pathologic Lymphadenopathy

When localized adenopathy, organomegaly, or constitutional symptoms are present:

Imaging Studies

• Contrast-enhanced CT of chest, abdomen, and pelvis for initial staging 3
• FDG-PET/CT is more sensitive for extranodal disease but has higher false-positive rates in HIV due to opportunistic infections and immune deficiency-related lymphoid hyperplasia 1, 4, 3
• Consider brain MRI with contrast if neurologic symptoms present 5

Tissue Diagnosis

• Fine-needle aspiration cytology (FNAC) offers simple, effective initial sampling for cytological evaluation 2
• Excisional lymph node biopsy evaluated by expert hematopathologist using immunohistochemistry and molecular techniques is required for definitive diagnosis 3, 6
• Stains should include: Leishman-Giemsa, Ziehl-Neelsen (for AFB), Papanicolaou, and Gram stains 2
• Mycobacterial culture on Löwenstein-Jensen medium is more sensitive than routine ZN staining for tuberculosis diagnosis 2

Infectious Disease Workup

• Patients with cancer and HIV should have infectious disease workup for positive lymph nodes, especially with low CD4 counts and B symptoms 1
• Bone marrow biopsy for staging aggressive lymphomas 3
• CSF analysis (cytology and flow cytometry) for aggressive non-Hodgkin lymphoma 3

Common Etiologies by Frequency

The differential diagnosis includes:

Infectious Causes (Most Common)

• Tuberculosis: Most common pathologic cause (28-60% of cases), increases with lower CD4 counts 2, 6
• Mycobacterium avium complex: Most common with CD4 ≤50 cells/μL 2
• Nontuberculous mycobacterial infections 7
• Fungal infections (histoplasmosis, cryptococcosis) 2
• HIV infection itself causing reactive hyperplasia 7, 2

Neoplastic Causes

• Non-Hodgkin lymphoma: 29% of biopsied cases, predominantly diffuse large B-cell or Burkitt type 2, 6
• Hodgkin lymphoma: 6% of cases, mixed cellularity subtype most common, nearly 90% EBV-associated 1, 6
• Kaposi sarcoma 1, 7
• Castleman disease 7

Reactive/Inflammatory

• Persistent generalized lymphadenopathy (benign): 19% of biopsied cases, characterized by follicular hyperplasia 2, 6
• Immune reconstitution inflammatory syndrome (IRIS) 8, 7

Treatment Approach

For Benign Persistent Generalized Lymphadenopathy

• No specific treatment required; observation only 1
• Initiate or optimize antiretroviral therapy (ART) to achieve viral suppression 3
• Monitor for development of localized adenopathy or constitutional symptoms 1

For Tuberculosis

• Start standard anti-tuberculous therapy immediately when diagnosed 6
• Continue ART throughout TB treatment 3
• Isoniazid preventive therapy for PPD ≥5 mm after active TB excluded 1

For HIV-Associated Lymphomas

• Initiate or optimize ART immediately and continue during chemotherapy 3
• For aggressive non-Hodgkin lymphoma: Full-dose intensive chemotherapy with rituximab for CD20-positive disease 3
• For Hodgkin lymphoma: ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) preferred due to lower toxicity 1, 3
• For primary CNS lymphoma: High-dose methotrexate (3 g/m²) with rituximab and concurrent ART 1, 3

Infection Prophylaxis During Treatment

• PCP prophylaxis strongly recommended for CD4 <200 cells/μL or during chemotherapy 3
• Antiviral prophylaxis (acyclovir/valacyclovir) for CD4 <200 cells/μL 3
• Consider antifungal prophylaxis (fluconazole) for CD4 <100 cells/μL 3

Critical Pitfalls to Avoid

• Never assume all lymphadenopathy in HIV is benign PGL; localized adenopathy requires tissue diagnosis 1
• Never delay tuberculosis evaluation in patients with positive PPD or clinical suspicion 1
• Never attribute FDG-PET positive lymph nodes solely to malignancy without considering opportunistic infections 1, 4
• Never modify cancer treatment based solely on HIV status; treat lymphomas as aggressively as in HIV-negative patients 1, 3
• Never discontinue ART during cancer treatment; maintain viral suppression throughout 3
• Avoid nephrotoxic drug combinations when using tenofovir-based ART regimens 8
• Monitor for immune reconstitution inflammatory syndrome (IRIS) after ART initiation, which may cause paradoxical worsening of lymphadenopathy 8, 7