Initial diagnostic steps for differentiating non-neoplastic causes of generalized lymphadenopathy
| Diagnostic example workup for differential of generalized lymphadenopathy . | ||
|---|---|---|
| All | • CBC • Chest radiograph • HIV-1/2 testing (antigen/antibody combination immunoassay) • SPEP • CRP/ESR | • Assessments of end-organ function (eg, creatinine, urinalysis, LFTs, coagulation studies, albumin) • Variable: US of LN, CT with IV contrast, 18F-FDG PET, LN biopsy (excisional biopsy is the gold standard for CD) |
| Infectious disease differential example workup (if indicated) | • Syphilis: RPR testing (nontreponemal) followed by confirmation with a treponemal test (eg, FTA-ABS) • HBV/HCV: HBV DNA PCR (or HBsAg with anti-HBc IgM antibody confirmation), HCV RNA PCR • EBV: heterophile antibody test (or VCA IgM/IgG [ELISA]) • Other pathogen-specific serology and PCR testing (depending on clinical indication): PCR: CMV (plasma, DNA), HHV8 (plasma, DNA), adenovirus (swab, DNA), HSV (swab/CSF/etc, DNA), HHV6 (plasma/tissue, DNA) ELISA (IgM/IgG): toxoplasmosis (or DNA PCR of tissue/plasma in immunocompromised) • Urine/serum antigen test (Histoplasma, Coccidioides, Cryptococcus) | • Atypical pathogen testing (if clinically indicated): leishmaniasis (DNA PCR), measles (RNA PCR), mumps (RNA PCR), rubella (RNA PCR), dengue (RNA PCR or NS1 antigen testing), Lyme disease (ELISA + Western blot for confirmation), leptospirosis (DNA PCR), brucellosis (DNA PCR), bartonellosis (DNA PCR), tularemia (DNA PCR), diphtheria (toxin PCR), plague (DNA PCR), ehrlichiosis (DNA PCR) • Sputum samples (if clinically indicated) • Blood cultures (with stain request including pathogens of interest) • LN histopathology specific tests (eg, LANA1 for HHV8) |
| Autoimmune differential example workup (if indicated) | • ANA (only if clinically indicated, due to false positives) • Disease-specific antibody testing (eg, anti-dsDNA, anti-Ro/SSA, anti-La/SS-B, rheumatoid factor, anti-CCP, anti-MPO, anti-PR3 if clinically indicated) • Serum complement levels (eg, C3, C4) • Serum immunoglobulin levels (eg, IgG1-4) • Genetic testing (eg, FAS/FASL/CASP10/NRAS/CASP8 mutations if ALPS is suspected) | • Flow cytometry for immune cell populations (eg, CD4/CD8 T cells in ALPS, if suspected) • Organ-specific imaging evaluation to assess organ involvement (disease specific) • Biopsy of other involved tissue (eg, skin) |
| Inflammatory disease differential example workup (if indicated) | • HLH: ferritin, triglycerides, sCD25, fibrinogen (additional specialized tests and tests to identify the trigger) • Disease-specific inflammatory biomarkers (eg, sIL-2RA, IL-18, CXCL9 for HLH) • Bone marrow examination (disease-specific studies; eg, evidence of hemophagocytosis for HLH) | • LN pathology–specific tests (S100, CD68, CD163, etc) • Serum eosinophils and IgE • Other genetic testing (eg, UBA1 gene sequencing for VEXAS) |
| Diagnostic example workup for differential of generalized lymphadenopathy . | ||
|---|---|---|
| All | • CBC • Chest radiograph • HIV-1/2 testing (antigen/antibody combination immunoassay) • SPEP • CRP/ESR | • Assessments of end-organ function (eg, creatinine, urinalysis, LFTs, coagulation studies, albumin) • Variable: US of LN, CT with IV contrast, 18F-FDG PET, LN biopsy (excisional biopsy is the gold standard for CD) |
| Infectious disease differential example workup (if indicated) | • Syphilis: RPR testing (nontreponemal) followed by confirmation with a treponemal test (eg, FTA-ABS) • HBV/HCV: HBV DNA PCR (or HBsAg with anti-HBc IgM antibody confirmation), HCV RNA PCR • EBV: heterophile antibody test (or VCA IgM/IgG [ELISA]) • Other pathogen-specific serology and PCR testing (depending on clinical indication): PCR: CMV (plasma, DNA), HHV8 (plasma, DNA), adenovirus (swab, DNA), HSV (swab/CSF/etc, DNA), HHV6 (plasma/tissue, DNA) ELISA (IgM/IgG): toxoplasmosis (or DNA PCR of tissue/plasma in immunocompromised) • Urine/serum antigen test (Histoplasma, Coccidioides, Cryptococcus) | • Atypical pathogen testing (if clinically indicated): leishmaniasis (DNA PCR), measles (RNA PCR), mumps (RNA PCR), rubella (RNA PCR), dengue (RNA PCR or NS1 antigen testing), Lyme disease (ELISA + Western blot for confirmation), leptospirosis (DNA PCR), brucellosis (DNA PCR), bartonellosis (DNA PCR), tularemia (DNA PCR), diphtheria (toxin PCR), plague (DNA PCR), ehrlichiosis (DNA PCR) • Sputum samples (if clinically indicated) • Blood cultures (with stain request including pathogens of interest) • LN histopathology specific tests (eg, LANA1 for HHV8) |
| Autoimmune differential example workup (if indicated) | • ANA (only if clinically indicated, due to false positives) • Disease-specific antibody testing (eg, anti-dsDNA, anti-Ro/SSA, anti-La/SS-B, rheumatoid factor, anti-CCP, anti-MPO, anti-PR3 if clinically indicated) • Serum complement levels (eg, C3, C4) • Serum immunoglobulin levels (eg, IgG1-4) • Genetic testing (eg, FAS/FASL/CASP10/NRAS/CASP8 mutations if ALPS is suspected) | • Flow cytometry for immune cell populations (eg, CD4/CD8 T cells in ALPS, if suspected) • Organ-specific imaging evaluation to assess organ involvement (disease specific) • Biopsy of other involved tissue (eg, skin) |
| Inflammatory disease differential example workup (if indicated) | • HLH: ferritin, triglycerides, sCD25, fibrinogen (additional specialized tests and tests to identify the trigger) • Disease-specific inflammatory biomarkers (eg, sIL-2RA, IL-18, CXCL9 for HLH) • Bone marrow examination (disease-specific studies; eg, evidence of hemophagocytosis for HLH) | • LN pathology–specific tests (S100, CD68, CD163, etc) • Serum eosinophils and IgE • Other genetic testing (eg, UBA1 gene sequencing for VEXAS) |
ALPS, autoimmune lymphoproliferative syndrome; CCP, cyclic citrullinated peptide; CSF, cerebrospinal fluid; FASL, FAS ligand; HBV, hepatitis B; HCV, hepatitis C; HLH, hemophagocytic lymphohistiocytosis; MPO, myeloperoxidase; US, ultrasound; VCA, viral capsid antigen.