Non-neoplastic causes of generalized lymphadenopathy on the differential for iMCD-TAFRO
| . | Non-neoplastic causes of generalized lymphadenopathy . | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| . | Autoimmune-related diseases on the differential . | Infectious diseases on the differential . | Inflammatory diseases on the differential . | ||||||
| . | SLE . | Sarcoidosis . | ALPS . | HIV infection . | Miliary TB . | Viral sepsis . | iMCD-TAFRO . | HLH . | MIS-C/A . |
| Laboratory assessments | |||||||||
| CRP | +/++ | +/++ | +/++ | +/++ | ++/+++ | ++/+++ | +++ | +++ | +++ |
| Hemoglobin‡ | Mild to moderate anemia | Mild to moderate anemia | Mild to severe anemia | Mild to moderate anemia | Moderate to severe anemia (varies) | Moderate to severe anemia (varies) | Moderate to severe anemia | Typically severe anemia | Mild to moderate anemia |
| Platelets | Thrombocytopenia | Aberrations uncommon (rare thrombocytopenia) | Thrombocytopenia | Thrombocytopenia | Thrombocytopenia in some | Thrombocytopenia often (mild to severe) | Severe thrombocytopenia | Severe thrombocytopenia | More commonly mild to moderate thrombocytopenia |
| WBC | Leukopenia | Leukopenia (BM involvement) | Neutropenia | Lymphopenia predominantly, neutropenia | Leukocytosis or leukocytopenia | Leukocytosis or leukopenia (can be severe), lymphopenia | Not a primary abnormality (leukocytosis in some) | Neutropenia | Leukocytosis and neutrophilia, lymphopenia common |
| LFTs | Uncommon elevated LFTs (most commonly non-immune related) | Mild elevation of LFTs (if liver involvement) | Elevated liver enzymes and ALP | Can have elevated liver enzymes (not typical presenting sign) | Elevated liver enzymes, hypoalbuminemia (if liver involvement) | Elevated liver enzymes, hypoalbuminemia | Elevated ALP without hyperbilirubinemia and transaminase elevation | Elevated transaminases and bilirubin; hypoalbuminemia and prolonged PT/INR and PTT | Elevated transaminases common |
| Immunoglobulins | Polyclonal hypergammaglobulinemia | Polyclonal hypergammaglobulinemia | Hypergammaglobulinemia | Hypogammaglobulinemia (late-stage) | Polyclonal hypergammaglobulinemia | Commonly hypogammaglobulinemia (but hypergammaglobulinemia in chronic/recurrent cases) | Normal, or mild hypergammaglobulinemia | Varies | Hypergammaglobulinemia common |
| Other unique laboratory features | ANA+ (98%), dsDNA+, renal insufficiency (lupus nephritis), hypocomplementemia | Hypercalcemia, elevated serum ACE (nonspecific) | Revealing genetic testing (FAS, FASL, CASP10, etc), elevated IL-10 and FASL, elevated double-negative T cells | HIV-1/2 positive on antigen/ antibody combination immunoassay | Hyponatremia (SIADH), hypercalcemia (granulomas) | Positive microbiological findings (eg, blood culture, CSF PCR); elevated IL-6 | Renal insufficiency; elevated IL-6, VEGF (variable) | Elevated ferritin, soluble CD25, triglycerides, and sIL-2R; low fibrinogen | Elevated ferritin, procalcitonin, IL-6; evidence of recent SARS-CoV2 infection |
| Clinical presentation | |||||||||
| Constitutional signs | +/++ | +/++ | +/++ | +/++ | ++/+++ | +++ | +++ | +++ | +++ |
| Organ involvement | Multiple (skin, renal, MSK/joints, cardiac) | Multiple (pulmonary, skin, eyes, cardiac) | Multiple (hepatosplenomegaly, autoimmune hematological and endocrine involvement) | Multiple (lymphoid tissue, CNS, GI, skin) | Multiple (pulmonary, hepatomegaly, spleen, bone marrow, CNS) | Multiple (renal dysfunction, cardiac dysfunction, respiratory failure, liver dysfunction) | Multiple (hepatosplenomegaly, renal, bone marrow) | Multiple (hepatosplenomegaly, bone marrow hemophagocytosis, inflammatory CNS findings) | Multiple (cardiac dysfunction, mucocutaneous, and GI involvement most common) |
| Exposure history risk | N/A | N/A | N/A | High-risk sexual activity, IV drug use | Health care/ correctional facilities, high TB burden areas, young age | Viral pathogen-specific exposures | N/A (HHV8-MCD associated with HHV8 risk factors) | N/A (infection-related exposure history for infection-related HLH) | Exposure to SARS-CoV-2-infected individuals |
| Additional unique features | Hallmark rash, photosensitivity, oral ulcers, arthritis, serositis | Ocular involvement (uveitis), erythema nodosum, hilar lymphadenopathy | Autoimmune endocrinopathies, autoimmune hematologic abnormalities (AIHA, ITP, etc), less commonly autoimmune | Oral candidiasis and recurrent opportunistic infections, retroviral seroconversion syndrome | Miliary pulmonary infiltrates, meningitis in some | Pathogen-specific viral exanthems, respiratory symptoms, and neurological symptoms | Anasarca and fluid accumulation (nonspecific), reticulin fibrosis in bone marrow, adrenal hemorrhage | Nearly all with hepatitis, 1/3 with generalized neurological findings, lymphadenopathy not as prominent | Temporal association with COVID infection; fever and GI symptoms most common |
| Lymph node pattern | |||||||||
| % Presenting with lymphadenopathy | 33%-69% | >90% (hilar) 20%-45% (hilar) | Part of diagnostic criteria | Common (up to 70%-90%) | Common (~50%-80%) | Occurs, but not usually primary feature (varies by pathogen) | Part of diagnostic criteria | ~30%-60% | Common (~50%-60%) |
| Primary presenting LN pattern | Generalized (majority) | Generalized (majority) | Generalized | Generalized | Generalized | Generalized | Generalized | Generalized | Generalized |
| Preferred LN stations | Cervical | Hilar | Fluctuates (cervical, axillary, inguinal; others also observed) | Cervical, axillary | Mediastinal, hilar, abdominal | Varies by pathogen (cervical common) | Varies | Varies (cervical, axillary, mediastinal, hilar, abdominal) | Cervical, axillary, inguinal |
| LN histology | Nonspecific findings (follicular hyperplasia, increased vascularity, scattered plasma cells); most specific finding: coagulative necrosis with hematoxylin bodies | Non-necrotizing noncaseating granulomas | Most commonly lymphoid hyperplasia, paracortical expansion | Morphological pattern depends on stage (eg, follicular hyperplasia, follicular involution, and diffuse pattern) | Necrotizing, caseating granulomas | Reactive changes (follicular and paracortical hyperplasia); EBV (atypical lymphocytes and B-cell proliferation) and CMV (owl-eye cells) have specific findings | Hypervascular or mixed subtype with germinal center regression, vascularity, and FDC prominence | Sinus histiocytosis and hemophagocytosis, histiocytic infiltration, paracortical expansion | Reactive hyperplasia |
| . | Non-neoplastic causes of generalized lymphadenopathy . | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| . | Autoimmune-related diseases on the differential . | Infectious diseases on the differential . | Inflammatory diseases on the differential . | ||||||
| . | SLE . | Sarcoidosis . | ALPS . | HIV infection . | Miliary TB . | Viral sepsis . | iMCD-TAFRO . | HLH . | MIS-C/A . |
| Laboratory assessments | |||||||||
| CRP | +/++ | +/++ | +/++ | +/++ | ++/+++ | ++/+++ | +++ | +++ | +++ |
| Hemoglobin‡ | Mild to moderate anemia | Mild to moderate anemia | Mild to severe anemia | Mild to moderate anemia | Moderate to severe anemia (varies) | Moderate to severe anemia (varies) | Moderate to severe anemia | Typically severe anemia | Mild to moderate anemia |
| Platelets | Thrombocytopenia | Aberrations uncommon (rare thrombocytopenia) | Thrombocytopenia | Thrombocytopenia | Thrombocytopenia in some | Thrombocytopenia often (mild to severe) | Severe thrombocytopenia | Severe thrombocytopenia | More commonly mild to moderate thrombocytopenia |
| WBC | Leukopenia | Leukopenia (BM involvement) | Neutropenia | Lymphopenia predominantly, neutropenia | Leukocytosis or leukocytopenia | Leukocytosis or leukopenia (can be severe), lymphopenia | Not a primary abnormality (leukocytosis in some) | Neutropenia | Leukocytosis and neutrophilia, lymphopenia common |
| LFTs | Uncommon elevated LFTs (most commonly non-immune related) | Mild elevation of LFTs (if liver involvement) | Elevated liver enzymes and ALP | Can have elevated liver enzymes (not typical presenting sign) | Elevated liver enzymes, hypoalbuminemia (if liver involvement) | Elevated liver enzymes, hypoalbuminemia | Elevated ALP without hyperbilirubinemia and transaminase elevation | Elevated transaminases and bilirubin; hypoalbuminemia and prolonged PT/INR and PTT | Elevated transaminases common |
| Immunoglobulins | Polyclonal hypergammaglobulinemia | Polyclonal hypergammaglobulinemia | Hypergammaglobulinemia | Hypogammaglobulinemia (late-stage) | Polyclonal hypergammaglobulinemia | Commonly hypogammaglobulinemia (but hypergammaglobulinemia in chronic/recurrent cases) | Normal, or mild hypergammaglobulinemia | Varies | Hypergammaglobulinemia common |
| Other unique laboratory features | ANA+ (98%), dsDNA+, renal insufficiency (lupus nephritis), hypocomplementemia | Hypercalcemia, elevated serum ACE (nonspecific) | Revealing genetic testing (FAS, FASL, CASP10, etc), elevated IL-10 and FASL, elevated double-negative T cells | HIV-1/2 positive on antigen/ antibody combination immunoassay | Hyponatremia (SIADH), hypercalcemia (granulomas) | Positive microbiological findings (eg, blood culture, CSF PCR); elevated IL-6 | Renal insufficiency; elevated IL-6, VEGF (variable) | Elevated ferritin, soluble CD25, triglycerides, and sIL-2R; low fibrinogen | Elevated ferritin, procalcitonin, IL-6; evidence of recent SARS-CoV2 infection |
| Clinical presentation | |||||||||
| Constitutional signs | +/++ | +/++ | +/++ | +/++ | ++/+++ | +++ | +++ | +++ | +++ |
| Organ involvement | Multiple (skin, renal, MSK/joints, cardiac) | Multiple (pulmonary, skin, eyes, cardiac) | Multiple (hepatosplenomegaly, autoimmune hematological and endocrine involvement) | Multiple (lymphoid tissue, CNS, GI, skin) | Multiple (pulmonary, hepatomegaly, spleen, bone marrow, CNS) | Multiple (renal dysfunction, cardiac dysfunction, respiratory failure, liver dysfunction) | Multiple (hepatosplenomegaly, renal, bone marrow) | Multiple (hepatosplenomegaly, bone marrow hemophagocytosis, inflammatory CNS findings) | Multiple (cardiac dysfunction, mucocutaneous, and GI involvement most common) |
| Exposure history risk | N/A | N/A | N/A | High-risk sexual activity, IV drug use | Health care/ correctional facilities, high TB burden areas, young age | Viral pathogen-specific exposures | N/A (HHV8-MCD associated with HHV8 risk factors) | N/A (infection-related exposure history for infection-related HLH) | Exposure to SARS-CoV-2-infected individuals |
| Additional unique features | Hallmark rash, photosensitivity, oral ulcers, arthritis, serositis | Ocular involvement (uveitis), erythema nodosum, hilar lymphadenopathy | Autoimmune endocrinopathies, autoimmune hematologic abnormalities (AIHA, ITP, etc), less commonly autoimmune | Oral candidiasis and recurrent opportunistic infections, retroviral seroconversion syndrome | Miliary pulmonary infiltrates, meningitis in some | Pathogen-specific viral exanthems, respiratory symptoms, and neurological symptoms | Anasarca and fluid accumulation (nonspecific), reticulin fibrosis in bone marrow, adrenal hemorrhage | Nearly all with hepatitis, 1/3 with generalized neurological findings, lymphadenopathy not as prominent | Temporal association with COVID infection; fever and GI symptoms most common |
| Lymph node pattern | |||||||||
| % Presenting with lymphadenopathy | 33%-69% | >90% (hilar) 20%-45% (hilar) | Part of diagnostic criteria | Common (up to 70%-90%) | Common (~50%-80%) | Occurs, but not usually primary feature (varies by pathogen) | Part of diagnostic criteria | ~30%-60% | Common (~50%-60%) |
| Primary presenting LN pattern | Generalized (majority) | Generalized (majority) | Generalized | Generalized | Generalized | Generalized | Generalized | Generalized | Generalized |
| Preferred LN stations | Cervical | Hilar | Fluctuates (cervical, axillary, inguinal; others also observed) | Cervical, axillary | Mediastinal, hilar, abdominal | Varies by pathogen (cervical common) | Varies | Varies (cervical, axillary, mediastinal, hilar, abdominal) | Cervical, axillary, inguinal |
| LN histology | Nonspecific findings (follicular hyperplasia, increased vascularity, scattered plasma cells); most specific finding: coagulative necrosis with hematoxylin bodies | Non-necrotizing noncaseating granulomas | Most commonly lymphoid hyperplasia, paracortical expansion | Morphological pattern depends on stage (eg, follicular hyperplasia, follicular involution, and diffuse pattern) | Necrotizing, caseating granulomas | Reactive changes (follicular and paracortical hyperplasia); EBV (atypical lymphocytes and B-cell proliferation) and CMV (owl-eye cells) have specific findings | Hypervascular or mixed subtype with germinal center regression, vascularity, and FDC prominence | Sinus histiocytosis and hemophagocytosis, histiocytic infiltration, paracortical expansion | Reactive hyperplasia |
Anemia: mild (10-12 g/dL); moderate (8-10 g/dL); severe (<8 g/dL). Ranges provided for each disease are estimated but do not preclude patient subsets outside this range.
AIHA, autoimmune hemolytic anemia; ALP, alkaline phosphatase; ALPS, autoimmune lymphoproliferative syndrome; BM, bone marrow; CMV, cytomegalovirus; FASL, FAS ligand; GI, gastrointestinal; HLH, hemophagocytic lymphohistiocytosis; MIS-C/A, multisystem inflammatory syndrome in children and adults; MSK, musculoskeletal; N/A, not applicable; PHGG, polyclonal hypergammaglobulinemia; PT/INR, prothrombin time/international normalized ratio; PTT, partial thromboplastin time; SARS‑CoV‑2, severe acute respiratory syndrome coronavirus 2; SIADH, syndrome of inappropriate antidiuretic hormone secretion; TB, tuberculosis; WBC, white blood cell.