What are the causes of multiple lymphadenopathy?

Causes of Multiple Lymphadenopathy

Multiple (generalized) lymphadenopathy—defined as involvement of two or more non-contiguous lymph node regions—typically indicates underlying systemic disease and requires a systematic evaluation to identify infectious, malignant, autoimmune, or immunologic etiologies. 1, 2

Infectious Causes

Bacterial Infections

• Encapsulated organisms (particularly Streptococcus pneumoniae and Haemophilus influenzae) cause recurring lymphadenopathy, especially in patients with underlying immune dysfunction or antibody deficiencies 1, 3
• Mycobacterial infections, particularly tuberculosis, should be considered in patients with persistent adenopathy accompanied by fever, night sweats, or weight loss 1
• Staphylococcus aureus and gram-negative pathogens occur more commonly in advanced disease states and during neutropenia 3

Viral Infections

• HIV infection causes generalized lymphadenopathy through multiple mechanisms including direct marrow suppression, immune-mediated destruction, and opportunistic infections 1, 4
• Epstein-Barr virus (EBV) and cytomegalovirus (CMV) produce lymphadenopathy, particularly in immunocompromised hosts 1
• EBV-related lymphoproliferative disorders present with lymphadenopathy as a leading clinical sign 5

Malignant Causes

Lymphoproliferative Disorders

• Chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma are primary causes of recurring lymphadenopathy, with lymphoma producing adenopathy through marrow infiltration, hypersplenism, or autoimmune mechanisms 1, 3, 4
• Multiple myeloma patients develop functional hypogammaglobulinemia despite elevated total immunoglobulin levels, predisposing to infections and lymphadenopathy 3
• Lymphoproliferative malignancies cause bone marrow infiltration with malignant cells, resulting in leukopenia and dysfunctional immune cell production 3

Metastatic Disease

• Metastatic solid tumors should be considered, particularly with supraclavicular or epitrochlear node involvement, as these locations are highly suspicious for malignancy 1, 2, 6

Primary Immunodeficiency Disorders

Antibody Deficiencies

• Common variable immunodeficiency (CVID) presents with lymphadenopathy in 15-20% of patients, representing the most common primary immunodeficiency category associated with recurring adenopathy 1, 5
• Other antibody deficiencies have lower prevalence but should be considered in the differential 5

Immune Dysregulation Syndromes

• Autoimmune lymphoproliferative syndrome (ALPS) characteristically presents with chronic lymphadenopathy, hepatosplenomegaly, and autoimmune cytopenias 7, 1, 5
• Activated phosphoinositide 3-kinase delta syndrome presents with lymphadenopathy as one of the leading clinical signs 5
• Combined immunodeficiency disorders, including Omenn syndrome (presenting in first months of life), feature lymphadenopathy prominently 5

Autoimmune and Inflammatory Conditions

Autoimmune Diseases

• Systemic lupus erythematosus and rheumatoid arthritis cause generalized lymphadenopathy through immune complex deposition and chronic inflammation 1

Autoinflammatory Disorders

• Mevalonate kinase deficiency presents with recurrent fever and lymphadenopathy 1
• PFAPA syndrome (Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis) and hyper-IgD syndrome have the highest prevalence of lymphadenopathies among autoinflammatory diseases 5

Granulomatous Diseases

• Sarcoidosis commonly presents with bilateral hilar lymphadenopathy; asymptomatic bilateral hilar adenopathy is confirmed as sarcoidosis in 85% of cases, though alternative diagnoses including tuberculosis (38%) and lymphoma (25%) must be excluded 7
• Sarcoidosis with Löfgren's syndrome, lupus pernio, or Heerfordt's syndrome has sufficiently high clinical suspicion that lymph node sampling may not be required 7

Secondary Immunodeficiency and Iatrogenic Causes

HIV/AIDS

• HIV infection with high viral loads and low CD4+ counts causes recurring lymphadenopathy through multiple mechanisms 1, 4

Medication-Induced

• Iatrogenic immunosuppression from methotrexate, corticosteroids, and chemotherapy agents increases infection risk and causes drug-induced lymphadenopathy 1, 4
• CAR T-cell therapy produces prolonged cytopenias and lymphadenopathy weeks to months after infusion 4
• Heavily pretreated patients receiving multiple chemotherapeutic regimens face dramatically increased infection risk, with nearly 90% experiencing serious infectious complications 3

Critical Diagnostic Approach

High-Risk Features Requiring Urgent Evaluation

• Supraclavicular, epitrochlear, popliteal, or iliac nodes are abnormal and highly suspicious for malignancy 1, 2, 6
• Nodes >2 cm, hard consistency, or matted/fused to surrounding structures indicate possible malignancy or granulomatous disease 8
• Systemic symptoms including fever, night sweats, and unintentional weight loss ("B symptoms") suggest lymphoma or other serious pathology 8, 2

Risk Stratification

• Age >40 years, male sex, and white race increase malignancy risk 2
• Duration >4 weeks without resolution warrants imaging and laboratory investigation 8, 2

Diagnostic Workup Priority

• Excisional biopsy is the diagnostic method of choice, allowing assessment of lymph node architecture plus histological, immunohistochemical, cytogenetic, and molecular investigations 9, 2, 6
• Laboratory studies should include complete blood count, C-reactive protein, erythrocyte sedimentation rate, and tuberculosis testing when lymphadenopathy persists beyond four weeks 8

Critical Pitfall to Avoid

• Never use corticosteroids empirically without an appropriate diagnosis, as they mask the histologic diagnosis of lymphoma or other malignancy 8, 2