What are the causes of recurring lymphadenopathy?

Causes of Recurring Lymphadenopathy

Recurring lymphadenopathy most commonly results from infectious etiologies, primary immunodeficiency disorders (PIDDs), autoimmune conditions, malignancies (particularly lymphoproliferative disorders), and secondary immunodeficiency states including HIV infection. 1

Infectious Causes

Bacterial infections are the most frequent cause of recurring lymphadenopathy, particularly in patients with underlying immune dysfunction:

• Encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae) cause recurrent sinopulmonary infections with associated lymphadenopathy, especially in antibody-deficient patients 1, 2
• Staphylococcus aureus and gram-negative pathogens occur more commonly in advanced immunodeficiency states 2
• Mycobacterial infections (tuberculosis, atypical mycobacteria) should be considered, particularly with persistent adenopathy and systemic symptoms 1

Viral infections frequently cause recurring lymphadenopathy:

• HIV infection directly causes lymphadenopathy through viremia, with higher viral loads and lower CD4+ counts increasing the likelihood of persistent adenopathy 1
• Epstein-Barr virus, cytomegalovirus, and herpes viruses can cause recurrent lymphadenopathy, particularly in immunocompromised hosts 1
• Opportunistic viral infections (CMV, HSV, VZV) occur in heavily immunosuppressed patients 2, 3

Other infectious agents include toxoplasmosis, fungal infections (histoplasmosis, cryptococcosis), and Pneumocystis jirovecii 1, 4

Primary Immunodeficiency Disorders

Antibody deficiencies are the most common PIDD category (approximately 50% of all PIDDs) and frequently present with recurring lymphadenopathy:

• Patients experience repetitive, severe, or refractory infections with organisms of low virulence 1
• Up to 26% of children older than 2 years with invasive pneumococcal disease have an identifiable primary immunodeficiency 1
• Hypogammaglobulinemia leads to recurrent sinopulmonary infections with associated reactive lymphadenopathy 2

Autoimmune Lymphoproliferative Syndrome (ALPS) is a specific PIDD causing chronic lymphadenopathy:

• Characterized by chronic (≥6 months) nonmalignant, noninfectious lymphadenopathy and/or splenomegaly 1
• Results from mutations in FAS, FAS ligand, caspase genes, or NRAS causing failure of lymphocyte apoptosis 1
• Associated with elevated CD3+TCR+ CD4-CD8- double-negative T cells (≥1.5% of total lymphocytes) 1
• Presents with multilineage cytopenias and increased risk of B-cell lymphoma 1

Combined immunodeficiencies and immune dysregulation disorders account for 10-20% of PIDDs and present with recurring lymphadenopathy as part of their clinical spectrum 1

Malignancies

Lymphoproliferative disorders are a critical cause of recurring lymphadenopathy:

• Chronic lymphocytic leukemia (CLL) causes hypogammaglobulinemia and T-cell exhaustion, leading to recurrent infections with associated lymphadenopathy 2
• Non-Hodgkin and Hodgkin lymphomas can present with waxing and waning adenopathy 1
• Multiple myeloma patients are functionally hypogammaglobulinemic despite elevated immunoglobulin levels 2
• Lymphoma risk is increased in patients with certain PIDDs, particularly those with immune dysregulation 1

Metastatic solid tumors should be considered, particularly with supraclavicular or epitrochlear node involvement 5, 6

Autoimmune and Inflammatory Conditions

Autoimmune diseases frequently cause recurring lymphadenopathy:

• Systemic lupus erythematosus, rheumatoid arthritis, and other connective tissue diseases 1
• Autoimmune cytopenias, inflammatory arthropathies, and vasculitides associated with PIDDs 1
• Rosai-Dorfman-Destombes disease can coexist with autoimmune conditions in 10% of cases 1

Autoinflammatory disorders including mevalonate kinase deficiency (Hyper IgD syndrome) present with recurrent fever and lymphadenopathy 7

Secondary Immunodeficiency

HIV/AIDS is a major cause of recurring lymphadenopathy through multiple mechanisms:

• Direct HIV viremia causes lymphadenopathy, more common with higher viral loads and lower CD4+ counts 1
• Opportunistic infections (toxoplasmosis, cryptococcosis, tuberculosis, MAC) cause persistent adenopathy 1
• HIV-associated malignancies including Kaposi sarcoma and lymphoma 1

Iatrogenic immunosuppression from medications (methotrexate, corticosteroids, chemotherapy) increases infection risk and can cause drug-induced lymphadenopathy:

• Methotrexate specifically causes lymphadenopathy and lymphoproliferative disorders (including reversible forms) 3
• Immunosuppressive therapies predispose to opportunistic infections with associated adenopathy 1
• Heavily pretreated patients with lymphoproliferative disorders face dramatically increased infection risk (nearly 90% experience serious infectious complications) 2

Other causes of secondary immunodeficiency include malnutrition, protein-losing disorders, infiltrative diseases, and extremes of age 1

Critical Diagnostic Approach

When evaluating recurring lymphadenopathy, prioritize these assessments:

• Duration ≥2 weeks raises concern for malignancy; persistence ≥4-6 weeks without diagnosis mandates biopsy 5, 6
• Node characteristics: size >1.5-2 cm, firm/hard consistency, fixed/matted nodes, supraclavicular or epitrochlear location are suspicious 5, 6
• Systemic symptoms (fever, night sweats, unintentional weight loss) suggest malignancy or systemic disease 1, 5, 6
• Family history of recurrent infections, early childhood deaths, or diagnosed PIDDs points toward inherited immunodeficiency 1
• Immunologic evaluation including complete blood count, immunoglobulin levels, and lymphocyte subsets when PIDD suspected 1
• HIV testing when risk factors present or unexplained persistent adenopathy 1, 5
• Imaging (ultrasound initially, CT/MRI for deep involvement) to characterize nodes and identify additional pathology 5, 6

Critical pitfalls to avoid:

• Never dismiss persistent lymphadenopathy (>2 months) without proper evaluation, particularly in children and young adults 5
• Do not give empiric antibiotics without evidence of infection, as this delays diagnosis of malignancy 5, 6
• In HIV-positive patients or those with low CD4+ counts, always perform infectious disease workup for positive lymph nodes before attributing to malignancy 1
• Avoid corticosteroids without definitive diagnosis, as they mask histologic findings of lymphoma 6, 8
• Biopsy lesions of uncertain etiology to confirm diagnosis rather than assuming benign etiology 1
• Do not underestimate infection risk in patients with lymphoproliferative disorders even when disease appears controlled 2