Multicentric Castleman Disease

Complex MONDO:0019754 Lymphoproliferative Disease Autoimmune Disease

A rare lymphoproliferative disorder characterized by systemic lymphadenopathy with characteristic histopathological features including angiofollicular lymph node hyperplasia. Multicentric Castleman disease (MCD) can be driven by human herpesvirus 8 (HHV-8) infection or occur as an idiopathic form (iMCD). The pathogenesis centers on dysregulated interleukin-6 (IL-6) signaling leading to systemic inflammation, constitutional symptoms, cytopenias, and multi-organ dysfunction. IL-6 targeting with siltuximab or tocilizumab has transformed treatment outcomes.

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2
Pathophys.
11
Phenotypes
4
Treatments
2
Subtypes
18
References
1
Deep Research
◆

Subtypes

2
HHV-8 Associated MCD
Form driven by human herpesvirus 8 (HHV-8/KSHV) infection, which produces viral IL-6 (vIL-6) that activates the JAK-STAT signaling pathway. More common in immunocompromised individuals, particularly those with HIV.
Show evidence (1 reference)
PMID:37288720 SUPPORT Human Clinical
"Rituximab has revolutionized the treatment of Kaposi sarcoma-associated herpesvirus/human herpesvirus 8-associated multicentric Castleman disease (HHV8+ MCD), converting a rapidly fatal illness into a relapsing disease. HHV8+ MCD mainly affects patients with HIV infection but can also be..."
Confirms HHV-8 associated MCD as a distinct subtype predominantly affecting HIV-positive patients.
Idiopathic MCD (iMCD)
Form without HHV-8 infection, driven by endogenous IL-6 overproduction from an unknown trigger. Further subdivided into iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, organomegaly) and iMCD-NOS (not otherwise specified).
Show evidence (2 references)
PMID:24622327 SUPPORT Human Clinical
"There is also a group of HIV-negative and HHV-8-negative patients with unknown etiology and pathophysiology, which we propose referring to as idiopathic MCD (iMCD)."
Defines the concept of idiopathic MCD as distinct from HHV-8-driven MCD.
PMID:29157612 SUPPORT Human Clinical
"TAFRO syndrome is a newly recognized variant of idiopathic multicentric Castleman disease (iMCD) that involves a constellation of syndromes: thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O)."
Defines iMCD-TAFRO as a recognized subvariant with characteristic clinical features.
⚙

Pathophysiology

2
IL-6 Hypersecretion and Cytokine Storm
Dysregulated overproduction of interleukin-6 drives the systemic inflammatory manifestations of MCD. In HHV-8-associated MCD, the virus produces viral IL-6 (vIL-6) that mimics human IL-6. In iMCD, the source of IL-6 overproduction remains unclear but may involve autoimmune mechanisms, paraneoplastic cytokine secretion, or non-HHV-8 viral triggers. IL-6 activates JAK-STAT3 signaling, driving B-cell proliferation, plasmacytosis, acute phase protein production, and vascular endothelial growth factor (VEGF) release.
B cell link Plasma cell link
Interleukin-6-mediated signaling pathway link JAK-STAT signaling link
Show evidence (3 references)
PMID:25042199 SUPPORT Human Clinical
"Multicentric Castleman's disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6."
The pivotal siltuximab trial establishes IL-6 dysregulation as the central driver of MCD.
PMID:24622327 SUPPORT Human Clinical
"Multicentric Castleman's disease (MCD) describes a heterogeneous group of disorders involving proliferation of morphologically benign lymphocytes due to excessive proinflammatory hypercytokinemia, most notably of interleukin-6."
Confirms IL-6 hypercytokinemia as the central pathogenic mechanism in MCD.
PMID:24622327 SUPPORT Human Clinical
"We propose that 1 or more of the following 3 candidate processes may drive iMCD hypercytokinemia: systemic inflammatory disease mechanisms via autoantibodies or inflammatory gene mutations, paraneoplastic syndrome mechanisms via ectopic cytokine secretion, and/or a non-HHV-8 virus."
Proposes three candidate processes that may drive IL-6 hypersecretion in idiopathic MCD.
Angiogenesis and Vascular Proliferation
IL-6-driven VEGF overproduction causes exuberant angiogenesis in affected lymph nodes, producing the characteristic angiofollicular hyperplasia. This vascular proliferation contributes to organomegaly and fluid retention.
Angiogenesis link
Show evidence (1 reference)
PMID:24622327 PARTIAL Human Clinical
"Patients demonstrate intense episodes of systemic inflammatory symptoms, polyclonal lymphocyte and plasma cell proliferation, autoimmune manifestations, and organ system impairment."
Describes the systemic effects of hypercytokinemia including organ impairment, consistent with VEGF-driven vascular pathology.
●

Phenotypes

11
Blood 2
Anemia VERY_FREQUENT Anemia (HP:0001903)
Show evidence (1 reference)
PMID:25042199 SUPPORT Human Clinical
"The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three)."
Anemia is a common hematologic manifestation in MCD patients.
Thrombocytopenia FREQUENT Thrombocytopenia (HP:0001873)
Particularly prominent in the TAFRO subtype of iMCD, where it is a defining feature.
Show evidence (1 reference)
PMID:29157612 SUPPORT Human Clinical
"Thrombocytopenia and severe anasarca accompanied by relatively low serum immunoglobulin levels are characteristic clinical findings of TAFRO syndrome that are not present in iMCD-not otherwise specified (iMCD-NOS)."
Thrombocytopenia is a characteristic feature of iMCD-TAFRO.
Cardiovascular 2
Generalized Lymphadenopathy VERY_FREQUENT Generalized lymphadenopathy (HP:0008940)
Show evidence (1 reference)
PMID:30181172 SUPPORT Human Clinical
"Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement."
Multicentric lymph node enlargement is the defining feature of MCD.
Splenomegaly FREQUENT Splenomegaly (HP:0001744)
Digestive 1
Hepatomegaly FREQUENT Hepatomegaly (HP:0002240)
Genitourinary 1
Renal Insufficiency OCCASIONAL Renal insufficiency (HP:0000083)
Metabolism 2
Fever VERY_FREQUENT Recurrent fever (HP:0001954)
Show evidence (1 reference)
PMID:29157612 SUPPORT Human Clinical
"TAFRO syndrome is a newly recognized variant of idiopathic multicentric Castleman disease (iMCD) that involves a constellation of syndromes: thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O)."
Fever is a defining feature of the TAFRO subtype and is common across all MCD subtypes.
Generalized Edema FREQUENT Generalized edema (HP:0007430)
Anasarca (severe generalized edema) is a defining feature of the TAFRO subtype. Can include pleural effusions, ascites, and peripheral edema.
Show evidence (1 reference)
PMID:29157612 SUPPORT Human Clinical
"Thrombocytopenia and severe anasarca accompanied by relatively low serum immunoglobulin levels are characteristic clinical findings of TAFRO syndrome"
Severe anasarca is a hallmark of iMCD-TAFRO.
Constitutional 2
Night Sweats FREQUENT Night sweats (HP:0030166)
Show evidence (1 reference)
PMID:25042199 SUPPORT Human Clinical
"The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three)."
Night sweats listed as a common symptom in MCD patients in the siltuximab trial.
Fatigue VERY_FREQUENT Fatigue (HP:0012378)
Show evidence (1 reference)
PMID:25042199 SUPPORT Human Clinical
"The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three)."
Fatigue listed as one of the most common symptoms in the siltuximab clinical trial.
Growth 1
Weight Loss FREQUENT Weight loss (HP:0001824)
💊

Treatments

4
Siltuximab
Action: anti-IL-6 monoclonal antibody therapy Ontology label: Pharmacotherapy NCIT:C15986
Anti-IL-6 monoclonal antibody that directly binds and neutralizes IL-6. FDA-approved for iMCD. In the pivotal randomized trial, durable tumor and symptomatic responses occurred in 34% of siltuximab-treated patients versus 0% with placebo.
Show evidence (2 references)
PMID:25042199 SUPPORT Human Clinical
"Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34·0%, 95% CI 11·1-54·8, p=0·0012)."
Pivotal randomized controlled trial demonstrating siltuximab efficacy in iMCD.
PMID:25042199 SUPPORT Human Clinical
"Siltuximab plus best supportive care was superior to best supportive care alone for patients with symptomatic multicentric Castleman's disease and well tolerated with prolonged exposure. Siltuximab is an important new treatment option for this disease."
Trial conclusion establishing siltuximab as a key treatment for MCD.
Tocilizumab
Action: anti-IL-6 receptor monoclonal antibody therapy Ontology label: Pharmacotherapy NCIT:C15986
Anti-IL-6 receptor monoclonal antibody that blocks IL-6 signaling. Approved in Japan for MCD treatment. Recommended as an alternative to siltuximab when siltuximab is unavailable.
Show evidence (1 reference)
PMID:30181172 SUPPORT Human Clinical
"The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD."
International consensus guidelines recommend tocilizumab as alternative first-line therapy for iMCD.
Rituximab
Action: rituximab therapy Ontology label: Pharmacotherapy NCIT:C15986
Anti-CD20 monoclonal antibody used as first-line therapy for HHV-8 associated MCD. Depletes B cells harboring HHV-8 virus. Has converted HHV-8+ MCD from a rapidly fatal illness to a relapsing disease with markedly improved survival.
Show evidence (3 references)
PMID:21778341 SUPPORT Human Clinical
"Clinical outcome and overall survival of HIV-MCD have markedly improved with rituximab-based therapies, considering rituximab-based therapies (with or without cytostatic agents) to be among the preferred first-line options in patients with HIV-MCD."
Multicenter retrospective study demonstrating improved outcomes with rituximab in HIV-associated MCD.
PMID:37288720 SUPPORT Human Clinical
"Rituximab has revolutionized the treatment of Kaposi sarcoma-associated herpesvirus/human herpesvirus 8-associated multicentric Castleman disease (HHV8+ MCD), converting a rapidly fatal illness into a relapsing disease."
Confirms rituximab as transformative therapy for HHV-8+ MCD.
PMID:37288720 SUPPORT Human Clinical
"Ninety-five patients (70 HIV+ and 25 HIV-) achieved complete remission (CR) after rituximab-based therapy."
Demonstrates high complete remission rates with rituximab-based therapy across both HIV+ and HIV- HHV8+ MCD patients.
Combination Chemotherapy
Action: chemotherapy MAXO:0000647
Adjuvant combination chemotherapy is recommended in the most severe iMCD cases, particularly when anti-IL-6 therapy alone is insufficient.
Show evidence (1 reference)
PMID:30181172 SUPPORT Human Clinical
"In the most severe cases, adjuvant combination chemotherapy is recommended."
International consensus guidelines recommend chemotherapy for severe refractory iMCD.
🔬

Biochemical Markers

3
Interleukin-6 (IL-6) (Elevated)
Context: Markedly elevated serum IL-6 levels drive the systemic inflammatory manifestations. IL-6 levels correlate with disease activity and severity.
Show evidence (1 reference)
PMID:25042199 SUPPORT Human Clinical
"Multicentric Castleman's disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6."
Establishes IL-6 as the central pathogenic cytokine in MCD.
C-Reactive Protein (CRP) (Elevated)
Context: Elevated as an acute phase reactant driven by IL-6 signaling. CRP levels serve as a biomarker for disease activity and progression risk.
Show evidence (1 reference)
PMID:37288720 SUPPORT Human Clinical
"serum C-reactive protein (CRP) >20 mg/mL were independently associated with an increased risk of progression after rituximab-induced CR"
CRP identified as an independent prognostic factor for disease progression in HHV8+ MCD.
VEGF (Elevated)
Context: Vascular endothelial growth factor is elevated due to IL-6-driven production, contributing to angiogenesis and vascular leak.
{ }

Source YAML

click to show 
name: Multicentric Castleman Disease
creation_date: "2026-03-06T00:00:00Z"
updated_date: "2026-05-10T13:07:07Z"
category: Complex
disease_term:
  preferred_term: multicentric Castleman disease
  term:
    id: MONDO:0019754
    label: multicentric Castleman disease
parents:
- Lymphoproliferative Disease
- Autoimmune Disease
description: >-
  A rare lymphoproliferative disorder characterized by systemic lymphadenopathy
  with characteristic histopathological features including angiofollicular
  lymph node hyperplasia. Multicentric Castleman disease (MCD) can be driven by
  human herpesvirus 8 (HHV-8) infection or occur as an idiopathic form (iMCD).
  The pathogenesis centers on dysregulated interleukin-6 (IL-6) signaling leading
  to systemic inflammation, constitutional symptoms, cytopenias, and multi-organ
  dysfunction. IL-6 targeting with siltuximab or tocilizumab has transformed
  treatment outcomes.
has_subtypes:
- name: HHV-8 Associated MCD
  description: >-
    Form driven by human herpesvirus 8 (HHV-8/KSHV) infection, which produces
    viral IL-6 (vIL-6) that activates the JAK-STAT signaling pathway. More
    common in immunocompromised individuals, particularly those with HIV.
  evidence:
  - reference: PMID:37288720
    reference_title: "Higher rate of progression in HIV- than in HIV+ patients after rituximab for HHV8+ multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rituximab has revolutionized the treatment of Kaposi sarcoma-associated
      herpesvirus/human herpesvirus 8-associated multicentric Castleman disease
      (HHV8+ MCD), converting a rapidly fatal illness into a relapsing disease.
      HHV8+ MCD mainly affects patients with HIV infection but can also be
      observed in patients without HIV infection.
    explanation: >-
      Confirms HHV-8 associated MCD as a distinct subtype predominantly
      affecting HIV-positive patients.
- name: Idiopathic MCD (iMCD)
  description: >-
    Form without HHV-8 infection, driven by endogenous IL-6 overproduction
    from an unknown trigger. Further subdivided into iMCD-TAFRO
    (thrombocytopenia, anasarca, fever, reticulin fibrosis, organomegaly)
    and iMCD-NOS (not otherwise specified).
  evidence:
  - reference: PMID:24622327
    reference_title: "HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is also a group of HIV-negative and HHV-8-negative patients with
      unknown etiology and pathophysiology, which we propose referring to as
      idiopathic MCD (iMCD).
    explanation: >-
      Defines the concept of idiopathic MCD as distinct from HHV-8-driven MCD.
  - reference: PMID:29157612
    reference_title: "TAFRO Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TAFRO syndrome is a newly recognized variant of idiopathic multicentric
      Castleman disease (iMCD) that involves a constellation of syndromes:
      thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R),
      and organomegaly (O).
    explanation: >-
      Defines iMCD-TAFRO as a recognized subvariant with characteristic
      clinical features.
pathophysiology:
- name: IL-6 Hypersecretion and Cytokine Storm
  description: >-
    Dysregulated overproduction of interleukin-6 drives the systemic
    inflammatory manifestations of MCD. In HHV-8-associated MCD, the virus
    produces viral IL-6 (vIL-6) that mimics human IL-6. In iMCD, the source
    of IL-6 overproduction remains unclear but may involve autoimmune mechanisms,
    paraneoplastic cytokine secretion, or non-HHV-8 viral triggers. IL-6
    activates JAK-STAT3 signaling, driving B-cell proliferation, plasmacytosis,
    acute phase protein production, and vascular endothelial growth factor
    (VEGF) release.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: Plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  biological_processes:
  - preferred_term: Interleukin-6-mediated signaling pathway
    term:
      id: GO:0070102
      label: interleukin-6-mediated signaling pathway
  - preferred_term: JAK-STAT signaling
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
  evidence:
  - reference: PMID:25042199
    reference_title: "Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Multicentric Castleman's disease is a rare lymphoproliferative disorder
      driven by dysregulated production of interleukin 6.
    explanation: >-
      The pivotal siltuximab trial establishes IL-6 dysregulation as the
      central driver of MCD.
  - reference: PMID:24622327
    reference_title: "HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Multicentric Castleman's disease (MCD) describes a heterogeneous group
      of disorders involving proliferation of morphologically benign lymphocytes
      due to excessive proinflammatory hypercytokinemia, most notably of
      interleukin-6.
    explanation: >-
      Confirms IL-6 hypercytokinemia as the central pathogenic mechanism in MCD.
  - reference: PMID:24622327
    reference_title: "HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We propose that 1 or more of the following 3 candidate processes may
      drive iMCD hypercytokinemia: systemic inflammatory disease mechanisms
      via autoantibodies or inflammatory gene mutations, paraneoplastic
      syndrome mechanisms via ectopic cytokine secretion, and/or a non-HHV-8
      virus.
    explanation: >-
      Proposes three candidate processes that may drive IL-6 hypersecretion
      in idiopathic MCD.
- name: Angiogenesis and Vascular Proliferation
  description: >-
    IL-6-driven VEGF overproduction causes exuberant angiogenesis in affected
    lymph nodes, producing the characteristic angiofollicular hyperplasia. This
    vascular proliferation contributes to organomegaly and fluid retention.
  biological_processes:
  - preferred_term: Angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
  evidence:
  - reference: PMID:24622327
    reference_title: "HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients demonstrate intense episodes of systemic inflammatory symptoms,
      polyclonal lymphocyte and plasma cell proliferation, autoimmune
      manifestations, and organ system impairment.
    explanation: >-
      Describes the systemic effects of hypercytokinemia including organ
      impairment, consistent with VEGF-driven vascular pathology.
phenotypes:
- category: Constitutional
  name: Generalized Lymphadenopathy
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:30181172
    reference_title: "International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Castleman disease (CD) describes a group of heterogeneous hematologic
      disorders with characteristic histopathological features. CD can present
      with unicentric or multicentric (MCD) regions of lymph node enlargement.
    explanation: >-
      Multicentric lymph node enlargement is the defining feature of MCD.
  phenotype_term:
    preferred_term: Generalized lymphadenopathy
    term:
      id: HP:0008940
      label: Generalized lymphadenopathy
- category: Constitutional
  name: Fever
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:29157612
    reference_title: "TAFRO Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TAFRO syndrome is a newly recognized variant of idiopathic multicentric
      Castleman disease (iMCD) that involves a constellation of syndromes:
      thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R),
      and organomegaly (O).
    explanation: >-
      Fever is a defining feature of the TAFRO subtype and is common across
      all MCD subtypes.
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
- category: Constitutional
  name: Night Sweats
  frequency: FREQUENT
  evidence:
  - reference: PMID:25042199
    reference_title: "Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common grade 3 or higher were fatigue (five vs one), night
      sweats (four vs one), and anaemia (one vs three).
    explanation: >-
      Night sweats listed as a common symptom in MCD patients in the
      siltuximab trial.
  phenotype_term:
    preferred_term: Night sweats
    term:
      id: HP:0030166
      label: Night sweats
- category: Constitutional
  name: Weight Loss
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
- category: Constitutional
  name: Fatigue
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25042199
    reference_title: "Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common grade 3 or higher were fatigue (five vs one), night
      sweats (four vs one), and anaemia (one vs three).
    explanation: >-
      Fatigue listed as one of the most common symptoms in the siltuximab
      clinical trial.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- category: Hematologic
  name: Anemia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25042199
    reference_title: "Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common grade 3 or higher were fatigue (five vs one), night
      sweats (four vs one), and anaemia (one vs three).
    explanation: >-
      Anemia is a common hematologic manifestation in MCD patients.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
- category: Hematologic
  name: Thrombocytopenia
  frequency: FREQUENT
  notes: >-
    Particularly prominent in the TAFRO subtype of iMCD, where it is a
    defining feature.
  evidence:
  - reference: PMID:29157612
    reference_title: "TAFRO Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thrombocytopenia and severe anasarca accompanied by relatively low serum
      immunoglobulin levels are characteristic clinical findings of TAFRO
      syndrome that are not present in iMCD-not otherwise specified (iMCD-NOS).
    explanation: >-
      Thrombocytopenia is a characteristic feature of iMCD-TAFRO.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
- category: Abdominal
  name: Splenomegaly
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
- category: Abdominal
  name: Hepatomegaly
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
- category: Constitutional
  name: Generalized Edema
  frequency: FREQUENT
  notes: >-
    Anasarca (severe generalized edema) is a defining feature of the TAFRO
    subtype. Can include pleural effusions, ascites, and peripheral edema.
  evidence:
  - reference: PMID:29157612
    reference_title: "TAFRO Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thrombocytopenia and severe anasarca accompanied by relatively low serum
      immunoglobulin levels are characteristic clinical findings of TAFRO
      syndrome
    explanation: >-
      Severe anasarca is a hallmark of iMCD-TAFRO.
  phenotype_term:
    preferred_term: Generalized edema
    term:
      id: HP:0007430
      label: Generalized edema
- category: Renal
  name: Renal Insufficiency
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
biochemical:
- name: Interleukin-6 (IL-6)
  presence: Elevated
  context: >-
    Markedly elevated serum IL-6 levels drive the systemic inflammatory
    manifestations. IL-6 levels correlate with disease activity and severity.
  evidence:
  - reference: PMID:25042199
    reference_title: "Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Multicentric Castleman's disease is a rare lymphoproliferative disorder
      driven by dysregulated production of interleukin 6.
    explanation: >-
      Establishes IL-6 as the central pathogenic cytokine in MCD.
- name: C-Reactive Protein (CRP)
  presence: Elevated
  context: >-
    Elevated as an acute phase reactant driven by IL-6 signaling. CRP levels
    serve as a biomarker for disease activity and progression risk.
  evidence:
  - reference: PMID:37288720
    reference_title: "Higher rate of progression in HIV- than in HIV+ patients after rituximab for HHV8+ multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      serum C-reactive protein (CRP) >20 mg/mL were independently associated
      with an increased risk of progression after rituximab-induced CR
    explanation: >-
      CRP identified as an independent prognostic factor for disease
      progression in HHV8+ MCD.
- name: VEGF
  presence: Elevated
  context: >-
    Vascular endothelial growth factor is elevated due to IL-6-driven
    production, contributing to angiogenesis and vascular leak.
treatments:
- name: Siltuximab
  description: >-
    Anti-IL-6 monoclonal antibody that directly binds and neutralizes IL-6.
    FDA-approved for iMCD. In the pivotal randomized trial, durable tumor and
    symptomatic responses occurred in 34% of siltuximab-treated patients versus
    0% with placebo.
  evidence:
  - reference: PMID:25042199
    reference_title: "Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Durable tumour and symptomatic responses occurred in 18 (34%) of 53
      patients in the siltuximab group and none of 26 in the placebo group
      (difference 34·0%, 95% CI 11·1-54·8, p=0·0012).
    explanation: >-
      Pivotal randomized controlled trial demonstrating siltuximab efficacy
      in iMCD.
  - reference: PMID:25042199
    reference_title: "Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Siltuximab plus best supportive care was superior to best supportive care
      alone for patients with symptomatic multicentric Castleman's disease and
      well tolerated with prolonged exposure. Siltuximab is an important new
      treatment option for this disease.
    explanation: >-
      Trial conclusion establishing siltuximab as a key treatment for MCD.
  treatment_term:
    preferred_term: anti-IL-6 monoclonal antibody therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Tocilizumab
  description: >-
    Anti-IL-6 receptor monoclonal antibody that blocks IL-6 signaling.
    Approved in Japan for MCD treatment. Recommended as an alternative to
    siltuximab when siltuximab is unavailable.
  evidence:
  - reference: PMID:30181172
    reference_title: "International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab,
      if siltuximab is not available) with or without corticosteroids is the
      preferred first-line therapy for iMCD.
    explanation: >-
      International consensus guidelines recommend tocilizumab as alternative
      first-line therapy for iMCD.
  treatment_term:
    preferred_term: anti-IL-6 receptor monoclonal antibody therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Rituximab
  description: >-
    Anti-CD20 monoclonal antibody used as first-line therapy for HHV-8
    associated MCD. Depletes B cells harboring HHV-8 virus. Has converted
    HHV-8+ MCD from a rapidly fatal illness to a relapsing disease with
    markedly improved survival.
  evidence:
  - reference: PMID:21778341
    reference_title: "Improved outcome with rituximab in patients with HIV-associated multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical outcome and overall survival of HIV-MCD have markedly improved
      with rituximab-based therapies, considering rituximab-based therapies
      (with or without cytostatic agents) to be among the preferred first-line
      options in patients with HIV-MCD.
    explanation: >-
      Multicenter retrospective study demonstrating improved outcomes with
      rituximab in HIV-associated MCD.
  - reference: PMID:37288720
    reference_title: "Higher rate of progression in HIV- than in HIV+ patients after rituximab for HHV8+ multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rituximab has revolutionized the treatment of Kaposi sarcoma-associated
      herpesvirus/human herpesvirus 8-associated multicentric Castleman disease
      (HHV8+ MCD), converting a rapidly fatal illness into a relapsing disease.
    explanation: >-
      Confirms rituximab as transformative therapy for HHV-8+ MCD.
  - reference: PMID:37288720
    reference_title: "Higher rate of progression in HIV- than in HIV+ patients after rituximab for HHV8+ multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ninety-five patients (70 HIV+ and 25 HIV-) achieved complete remission
      (CR) after rituximab-based therapy.
    explanation: >-
      Demonstrates high complete remission rates with rituximab-based therapy
      across both HIV+ and HIV- HHV8+ MCD patients.
  treatment_term:
    preferred_term: rituximab therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Combination Chemotherapy
  description: >-
    Adjuvant combination chemotherapy is recommended in the most severe iMCD
    cases, particularly when anti-IL-6 therapy alone is insufficient.
  evidence:
  - reference: PMID:30181172
    reference_title: "International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the most severe cases, adjuvant combination chemotherapy is
      recommended.
    explanation: >-
      International consensus guidelines recommend chemotherapy for severe
      refractory iMCD.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: MAXO:0000647
      label: chemotherapy
datasets:
references:
- reference: DOI:10.1016/j.bvth.2024.100006
  title: Idiopathic multicentric Castleman disease - TAFRO results in high levels of mTOR activator SVEP1, tissue factor, and endotheliopathy
  found_in:
  - Multicentric_Castleman_Disease-deep-research-falcon.md
  findings:
  - statement: Idiopathic multicentric Castleman disease - TAFRO results in high levels of mTOR activator SVEP1, tissue factor, and endotheliopathy
    supporting_text: Idiopathic multicentric Castleman disease - TAFRO results in high levels of mTOR activator SVEP1, tissue factor, and endotheliopathy
- reference: DOI:10.1016/j.hoc.2017.09.001
  title: Epidemiology of Castleman Disease
  found_in:
  - Multicentric_Castleman_Disease-deep-research-falcon.md
  findings:
  - statement: Epidemiology of Castleman Disease
    supporting_text: Epidemiology of Castleman Disease
- reference: DOI:10.1038/s41541-022-00535-4
  title: 'KSHV (HHV8) vaccine: promises and potential pitfalls for a new anti-cancer vaccine'
  found_in:
  - Multicentric_Castleman_Disease-deep-research-falcon.md
  findings:
  - statement: Seven viruses cause at least 15% of the total cancer burden.
    supporting_text: Seven viruses cause at least 15% of the total cancer burden.
    evidence:
    - reference: DOI:10.1038/s41541-022-00535-4
      reference_title: 'KSHV (HHV8) vaccine: promises and potential pitfalls for a new anti-cancer vaccine'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Seven viruses cause at least 15% of the total cancer burden.
      explanation: Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
- reference: DOI:10.1038/s41572-021-00317-7
  title: Castleman disease
  found_in:
  - Multicentric_Castleman_Disease-deep-research-falcon.md
  findings:
  - statement: Castleman disease
    supporting_text: Castleman disease
- reference: DOI:10.1111/tid.70179
  title: 'HHV‐8/KSHV in Solid Organ Transplantation: Current Gaps of Knowledge and Future Directions'
  found_in:
  - Multicentric_Castleman_Disease-deep-research-falcon.md
  findings:
  - statement: 'HHV‐8/KSHV in Solid Organ Transplantation: Current Gaps of Knowledge and Future Directions'
    supporting_text: The incidence of HHV‐8/KSHV–associated diseases (KADs) among solid organ transplant (SOT) recipients has shown a relative increase, likely reflecting the growing population of long‐term SOT survivors and heightened recognition and reporting due to greater clinician awareness.
    evidence:
    - reference: DOI:10.1111/tid.70179
      reference_title: 'HHV‐8/KSHV in Solid Organ Transplantation: Current Gaps of Knowledge and Future Directions'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The incidence of HHV‐8/KSHV–associated diseases (KADs) among solid organ transplant (SOT) recipients has shown a relative increase, likely reflecting the growing population of long‐term SOT survivors and heightened recognition and reporting due to greater clinician awareness.
      explanation: Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
- reference: DOI:10.1182/asheducation-2018.1.318
  title: Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease
  found_in:
  - Multicentric_Castleman_Disease-deep-research-falcon.md
  findings:
  - statement: Castleman disease (CD) describes a heterogeneous group of hematologic disorders that share characteristic lymph node histopathology.
    supporting_text: Castleman disease (CD) describes a heterogeneous group of hematologic disorders that share characteristic lymph node histopathology.
    evidence:
    - reference: DOI:10.1182/asheducation-2018.1.318
      reference_title: Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Castleman disease (CD) describes a heterogeneous group of hematologic disorders that share characteristic lymph node histopathology.
      explanation: Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
- reference: DOI:10.1182/blood-2016-10-746933
  title: International, evidence-based consensus diagnostic criteria for HHV-8–negative/idiopathic multicentric Castleman disease
  found_in:
  - Multicentric_Castleman_Disease-deep-research-falcon.md
  findings:
  - statement: Key Points An international panel established the first ever diagnostic criteria for iMCD based on review of 244 clinical cases and 88 tissue samples.
    supporting_text: Key Points An international panel established the first ever diagnostic criteria for iMCD based on review of 244 clinical cases and 88 tissue samples.
    evidence:
    - reference: DOI:10.1182/blood-2016-10-746933
      reference_title: International, evidence-based consensus diagnostic criteria for HHV-8–negative/idiopathic multicentric Castleman disease
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Key Points An international panel established the first ever diagnostic criteria for iMCD based on review of 244 clinical cases and 88 tissue samples.
      explanation: Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
- reference: DOI:10.1182/bloodadvances.2021004441
  title: Epidemiology and treatment patterns of idiopathic multicentric Castleman disease in the era of IL-6–directed therapy
  found_in:
  - Multicentric_Castleman_Disease-deep-research-falcon.md
  findings:
  - statement: The epidemiology of human herpesvirus-8–negative/idiopathic multicentric Castleman disease (iMCD) remains incompletely understood.
    supporting_text: The epidemiology of human herpesvirus-8–negative/idiopathic multicentric Castleman disease (iMCD) remains incompletely understood.
    evidence:
    - reference: DOI:10.1182/bloodadvances.2021004441
      reference_title: Epidemiology and treatment patterns of idiopathic multicentric Castleman disease in the era of IL-6–directed therapy
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The epidemiology of human herpesvirus-8–negative/idiopathic multicentric Castleman disease (iMCD) remains incompletely understood.
      explanation: Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
- reference: DOI:10.1182/bloodadvances.2022007112
  title: Siltuximab is associated with improved progression-free survival in idiopathic multicentric Castleman disease
  found_in:
  - Multicentric_Castleman_Disease-deep-research-falcon.md
  findings:
  - statement: Idiopathic multicentric Castleman disease (iMCD) is a rare heterogeneous disorder involving multicentric lymphadenopathy, systemic inflammation, and cytokine-driven organ dysfunction.
    supporting_text: Idiopathic multicentric Castleman disease (iMCD) is a rare heterogeneous disorder involving multicentric lymphadenopathy, systemic inflammation, and cytokine-driven organ dysfunction.
    evidence:
    - reference: DOI:10.1182/bloodadvances.2022007112
      reference_title: Siltuximab is associated with improved progression-free survival in idiopathic multicentric Castleman disease
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Idiopathic multicentric Castleman disease (iMCD) is a rare heterogeneous disorder involving multicentric lymphadenopathy, systemic inflammation, and cytokine-driven organ dysfunction.
      explanation: Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
- reference: DOI:10.1182/bloodadvances.2024013548
  title: 'The clinical picture of Castleman disease: a systematic review and meta-analysis'
  found_in:
  - Multicentric_Castleman_Disease-deep-research-falcon.md
  findings:
  - statement: Castleman disease (CD) encompasses a spectrum of rare disorders, including unicentric CD (UCD), idiopathic multicentric CD (iMCD), and human herpesvirus 8–associated MCD (HHV8+ MCD).
    supporting_text: Castleman disease (CD) encompasses a spectrum of rare disorders, including unicentric CD (UCD), idiopathic multicentric CD (iMCD), and human herpesvirus 8–associated MCD (HHV8+ MCD).
    evidence:
    - reference: DOI:10.1182/bloodadvances.2024013548
      reference_title: 'The clinical picture of Castleman disease: a systematic review and meta-analysis'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Castleman disease (CD) encompasses a spectrum of rare disorders, including unicentric CD (UCD), idiopathic multicentric CD (iMCD), and human herpesvirus 8–associated MCD (HHV8+ MCD).
      explanation: Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
- reference: DOI:10.14740/jh1343
  title: 'Siltuximab in Idiopathic Multicentric Castleman Disease: Real-World Experience'
  found_in:
  - Multicentric_Castleman_Disease-deep-research-falcon.md
  findings:
  - statement: 'Siltuximab in Idiopathic Multicentric Castleman Disease: Real-World Experience'
    supporting_text: 'Siltuximab in Idiopathic Multicentric Castleman Disease: Real-World Experience'
- reference: PMID:39970477
  title: "Castleman's disease: one disease, multiple etiologies."
  found_in:
  - Multicentric_Castleman_Disease-deep-research-falcon.md
  findings:
  - statement: "Castleman's disease: one disease, multiple etiologies"
    supporting_text: "Castleman's disease: one disease, multiple etiologies"
- reference: DOI:10.3389/fmicb.2012.00073
  title: 'Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV–MCD) and the KSHV Inflammatory Cytokine Syndrome'
  found_in:
  - Multicentric_Castleman_Disease-deep-research-falcon.md
  findings:
  - statement: 'Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV–MCD) and the KSHV Inflammatory Cytokine Syndrome'
    supporting_text: 'Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV–MCD) and the KSHV Inflammatory Cytokine Syndrome'
- reference: DOI:10.3389/ti.2023.11856
  title: Prevention of Oncogenic Gammaherpesvirinae (EBV and HHV8) Associated Disease in Solid Organ Transplant Recipients
  found_in:
  - Multicentric_Castleman_Disease-deep-research-falcon.md
  findings:
  - statement: Long-term risk for malignancy is higher among solid organ transplant (SOT) recipients compared to the general population.
    supporting_text: Long-term risk for malignancy is higher among solid organ transplant (SOT) recipients compared to the general population.
    evidence:
    - reference: DOI:10.3389/ti.2023.11856
      reference_title: Prevention of Oncogenic Gammaherpesvirinae (EBV and HHV8) Associated Disease in Solid Organ Transplant Recipients
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Long-term risk for malignancy is higher among solid organ transplant (SOT) recipients compared to the general population.
      explanation: Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
- reference: DOI:10.3390/ijms25073775
  title: Molecular Features of HHV8 Monoclonal Microlymphoma Associated with Kaposi Sarcoma and Multicentric Castleman Disease in an HIV-Negative Patient
  found_in:
  - Multicentric_Castleman_Disease-deep-research-falcon.md
  findings:
  - statement: Molecular Features of HHV8 Monoclonal Microlymphoma Associated with Kaposi Sarcoma and Multicentric Castleman Disease in an HIV-Negative Patient
    supporting_text: Human herpesvirus 8 (HHV8)-associated diseases include Kaposi sarcoma (KS), multicentric Castleman disease (MCD), germinotropic lymphoproliferative disorder (GLPD), Kaposi sarcoma inflammatory cytokine syndrome (KICS), HHV8-positive diffuse large B-cell lymphoma (HHV8+ DLBCL), primary effusion lymphoma (PEL), and extra-cavitary PEL (ECPEL).
    evidence:
    - reference: DOI:10.3390/ijms25073775
      reference_title: Molecular Features of HHV8 Monoclonal Microlymphoma Associated with Kaposi Sarcoma and Multicentric Castleman Disease in an HIV-Negative Patient
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Human herpesvirus 8 (HHV8)-associated diseases include Kaposi sarcoma (KS), multicentric Castleman disease (MCD), germinotropic lymphoproliferative disorder (GLPD), Kaposi sarcoma inflammatory cytokine syndrome (KICS), HHV8-positive diffuse large B-cell lymphoma (HHV8+ DLBCL), primary effusion lymphoma (PEL), and extra-cavitary PEL (ECPEL).
      explanation: Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
- reference: DOI:10.3390/jcm14186563
  title: 'Castleman Disease and Kaposi Sarcoma: A Review of the Literature and a Case Series'
  found_in:
  - Multicentric_Castleman_Disease-deep-research-falcon.md
  findings:
  - statement: Castleman disease and Kaposi sarcoma (KS) are both associated with infection by human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV).
    supporting_text: Castleman disease and Kaposi sarcoma (KS) are both associated with infection by human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV).
    evidence:
    - reference: DOI:10.3390/jcm14186563
      reference_title: 'Castleman Disease and Kaposi Sarcoma: A Review of the Literature and a Case Series'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Castleman disease and Kaposi sarcoma (KS) are both associated with infection by human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV).
      explanation: Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
- reference: DOI:10.3390/lymphatics3030020
  title: A Review of KSHV/HHV8-Associated Neoplasms and Related Lymphoproliferative Lesions
  found_in:
  - Multicentric_Castleman_Disease-deep-research-falcon.md
  findings:
  - statement: A Review of KSHV/HHV8-Associated Neoplasms and Related Lymphoproliferative Lesions
    supporting_text: There has been extensive research on the KSHV/HHV8 virus, which has led to a better understanding of viral transmission, pathogenesis, viral-driven lymphoid proliferation, neoplastic transformation, and how we might combat these processes clinically.
    evidence:
    - reference: DOI:10.3390/lymphatics3030020
      reference_title: A Review of KSHV/HHV8-Associated Neoplasms and Related Lymphoproliferative Lesions
      supports: SUPPORT
      evidence_source: OTHER
      snippet: There has been extensive research on the KSHV/HHV8 virus, which has led to a better understanding of viral transmission, pathogenesis, viral-driven lymphoid proliferation, neoplastic transformation, and how we might combat these processes clinically.
      explanation: Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
- reference: DOI:10.7759/cureus.73156
  title: 'The Enigma of Idiopathic Multicentric Castleman Disease: An Elusive Diagnosis'
  found_in:
  - Multicentric_Castleman_Disease-deep-research-falcon.md
  findings:
  - statement: 'The Enigma of Idiopathic Multicentric Castleman Disease: An Elusive Diagnosis'
    supporting_text: 'The Enigma of Idiopathic Multicentric Castleman Disease: An Elusive Diagnosis'
📚

References & Deep Research

References

18
DOI:10.1016/j.bvth.2024.100006
Idiopathic multicentric Castleman disease - TAFRO results in high levels of mTOR activator SVEP1, tissue factor, and endotheliopathy
1 finding
Idiopathic multicentric Castleman disease - TAFRO results in high levels of mTOR activator SVEP1, tissue factor, and endotheliopathy
"Idiopathic multicentric Castleman disease - TAFRO results in high levels of mTOR activator SVEP1, tissue factor, and endotheliopathy"
DOI:10.1016/j.hoc.2017.09.001
Epidemiology of Castleman Disease
1 finding
Epidemiology of Castleman Disease
"Epidemiology of Castleman Disease"
DOI:10.1038/s41541-022-00535-4
KSHV (HHV8) vaccine: promises and potential pitfalls for a new anti-cancer vaccine
1 finding
Seven viruses cause at least 15% of the total cancer burden.
"Seven viruses cause at least 15% of the total cancer burden."
Show evidence (1 reference)
DOI:10.1038/s41541-022-00535-4 SUPPORT Human Clinical
"Seven viruses cause at least 15% of the total cancer burden."
Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
DOI:10.1038/s41572-021-00317-7
Castleman disease
1 finding
Castleman disease
"Castleman disease"
DOI:10.1111/tid.70179
HHV‐8/KSHV in Solid Organ Transplantation: Current Gaps of Knowledge and Future Directions
1 finding
HHV‐8/KSHV in Solid Organ Transplantation: Current Gaps of Knowledge and Future Directions
"The incidence of HHV‐8/KSHV–associated diseases (KADs) among solid organ transplant (SOT) recipients has shown a relative increase, likely reflecting the growing population of long‐term SOT survivors and heightened recognition and reporting due to greater clinician awareness."
Show evidence (1 reference)
DOI:10.1111/tid.70179 SUPPORT Human Clinical
"The incidence of HHV‐8/KSHV–associated diseases (KADs) among solid organ transplant (SOT) recipients has shown a relative increase, likely reflecting the growing population of long‐term SOT survivors and heightened recognition and reporting due to greater clinician awareness."
Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
DOI:10.1182/asheducation-2018.1.318
Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease
1 finding
Castleman disease (CD) describes a heterogeneous group of hematologic disorders that share characteristic lymph node histopathology.
"Castleman disease (CD) describes a heterogeneous group of hematologic disorders that share characteristic lymph node histopathology."
Show evidence (1 reference)
DOI:10.1182/asheducation-2018.1.318 SUPPORT Other
"Castleman disease (CD) describes a heterogeneous group of hematologic disorders that share characteristic lymph node histopathology."
Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
DOI:10.1182/blood-2016-10-746933
International, evidence-based consensus diagnostic criteria for HHV-8–negative/idiopathic multicentric Castleman disease
1 finding
Key Points An international panel established the first ever diagnostic criteria for iMCD based on review of 244 clinical cases and 88 tissue samples.
"Key Points An international panel established the first ever diagnostic criteria for iMCD based on review of 244 clinical cases and 88 tissue samples."
Show evidence (1 reference)
DOI:10.1182/blood-2016-10-746933 SUPPORT Other
"Key Points An international panel established the first ever diagnostic criteria for iMCD based on review of 244 clinical cases and 88 tissue samples."
Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
DOI:10.1182/bloodadvances.2021004441
Epidemiology and treatment patterns of idiopathic multicentric Castleman disease in the era of IL-6–directed therapy
1 finding
The epidemiology of human herpesvirus-8–negative/idiopathic multicentric Castleman disease (iMCD) remains incompletely understood.
"The epidemiology of human herpesvirus-8–negative/idiopathic multicentric Castleman disease (iMCD) remains incompletely understood."
Show evidence (1 reference)
DOI:10.1182/bloodadvances.2021004441 SUPPORT Human Clinical
"The epidemiology of human herpesvirus-8–negative/idiopathic multicentric Castleman disease (iMCD) remains incompletely understood."
Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
DOI:10.1182/bloodadvances.2022007112
Siltuximab is associated with improved progression-free survival in idiopathic multicentric Castleman disease
1 finding
Idiopathic multicentric Castleman disease (iMCD) is a rare heterogeneous disorder involving multicentric lymphadenopathy, systemic inflammation, and cytokine-driven organ dysfunction.
"Idiopathic multicentric Castleman disease (iMCD) is a rare heterogeneous disorder involving multicentric lymphadenopathy, systemic inflammation, and cytokine-driven organ dysfunction."
Show evidence (1 reference)
DOI:10.1182/bloodadvances.2022007112 SUPPORT Human Clinical
"Idiopathic multicentric Castleman disease (iMCD) is a rare heterogeneous disorder involving multicentric lymphadenopathy, systemic inflammation, and cytokine-driven organ dysfunction."
Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
DOI:10.1182/bloodadvances.2024013548
The clinical picture of Castleman disease: a systematic review and meta-analysis
1 finding
Castleman disease (CD) encompasses a spectrum of rare disorders, including unicentric CD (UCD), idiopathic multicentric CD (iMCD), and human herpesvirus 8–associated MCD (HHV8+ MCD).
"Castleman disease (CD) encompasses a spectrum of rare disorders, including unicentric CD (UCD), idiopathic multicentric CD (iMCD), and human herpesvirus 8–associated MCD (HHV8+ MCD)."
Show evidence (1 reference)
DOI:10.1182/bloodadvances.2024013548 SUPPORT Other
"Castleman disease (CD) encompasses a spectrum of rare disorders, including unicentric CD (UCD), idiopathic multicentric CD (iMCD), and human herpesvirus 8–associated MCD (HHV8+ MCD)."
Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
DOI:10.14740/jh1343
Siltuximab in Idiopathic Multicentric Castleman Disease: Real-World Experience
1 finding
Siltuximab in Idiopathic Multicentric Castleman Disease: Real-World Experience
"Siltuximab in Idiopathic Multicentric Castleman Disease: Real-World Experience"
PMID:39970477
Castleman's disease: one disease, multiple etiologies.
1 finding
Castleman's disease: one disease, multiple etiologies
"Castleman's disease: one disease, multiple etiologies"
DOI:10.3389/fmicb.2012.00073
Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV–MCD) and the KSHV Inflammatory Cytokine Syndrome
1 finding
Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV–MCD) and the KSHV Inflammatory Cytokine Syndrome
"Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV–MCD) and the KSHV Inflammatory Cytokine Syndrome"
DOI:10.3389/ti.2023.11856
Prevention of Oncogenic Gammaherpesvirinae (EBV and HHV8) Associated Disease in Solid Organ Transplant Recipients
1 finding
Long-term risk for malignancy is higher among solid organ transplant (SOT) recipients compared to the general population.
"Long-term risk for malignancy is higher among solid organ transplant (SOT) recipients compared to the general population."
Show evidence (1 reference)
DOI:10.3389/ti.2023.11856 SUPPORT Human Clinical
"Long-term risk for malignancy is higher among solid organ transplant (SOT) recipients compared to the general population."
Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
DOI:10.3390/ijms25073775
Molecular Features of HHV8 Monoclonal Microlymphoma Associated with Kaposi Sarcoma and Multicentric Castleman Disease in an HIV-Negative Patient
1 finding
Molecular Features of HHV8 Monoclonal Microlymphoma Associated with Kaposi Sarcoma and Multicentric Castleman Disease in an HIV-Negative Patient
"Human herpesvirus 8 (HHV8)-associated diseases include Kaposi sarcoma (KS), multicentric Castleman disease (MCD), germinotropic lymphoproliferative disorder (GLPD), Kaposi sarcoma inflammatory cytokine syndrome (KICS), HHV8-positive diffuse large B-cell lymphoma (HHV8+ DLBCL), primary effusion..."
Show evidence (1 reference)
DOI:10.3390/ijms25073775 SUPPORT Human Clinical
"Human herpesvirus 8 (HHV8)-associated diseases include Kaposi sarcoma (KS), multicentric Castleman disease (MCD), germinotropic lymphoproliferative disorder (GLPD), Kaposi sarcoma inflammatory cytokine syndrome (KICS), HHV8-positive diffuse large B-cell lymphoma (HHV8+ DLBCL), primary effusion..."
Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
DOI:10.3390/jcm14186563
Castleman Disease and Kaposi Sarcoma: A Review of the Literature and a Case Series
1 finding
Castleman disease and Kaposi sarcoma (KS) are both associated with infection by human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV).
"Castleman disease and Kaposi sarcoma (KS) are both associated with infection by human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV)."
Show evidence (1 reference)
DOI:10.3390/jcm14186563 SUPPORT Other
"Castleman disease and Kaposi sarcoma (KS) are both associated with infection by human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV)."
Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
DOI:10.3390/lymphatics3030020
A Review of KSHV/HHV8-Associated Neoplasms and Related Lymphoproliferative Lesions
1 finding
A Review of KSHV/HHV8-Associated Neoplasms and Related Lymphoproliferative Lesions
"There has been extensive research on the KSHV/HHV8 virus, which has led to a better understanding of viral transmission, pathogenesis, viral-driven lymphoid proliferation, neoplastic transformation, and how we might combat these processes clinically."
Show evidence (1 reference)
DOI:10.3390/lymphatics3030020 SUPPORT Other
"There has been extensive research on the KSHV/HHV8 virus, which has led to a better understanding of viral transmission, pathogenesis, viral-driven lymphoid proliferation, neoplastic transformation, and how we might combat these processes clinically."
Deep research cited this publication as relevant literature for Multicentric Castleman Disease.
DOI:10.7759/cureus.73156
The Enigma of Idiopathic Multicentric Castleman Disease: An Elusive Diagnosis
1 finding
The Enigma of Idiopathic Multicentric Castleman Disease: An Elusive Diagnosis
"The Enigma of Idiopathic Multicentric Castleman Disease: An Elusive Diagnosis"

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Disease Characteristics Research Template
Edison Scientific Literature 56 citations 2026-05-10T06:07:06.282467

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Multicentric Castleman Disease
  • MONDO ID: (if available)
  • Category: Complex

Research Objectives

Please provide a comprehensive research report on Multicentric Castleman Disease covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Multicentric Castleman Disease (MCD) — Comprehensive Disease Characteristics Report (2026-05-10)

Target disease

  • Disease name: Multicentric Castleman disease (MCD)
  • Category: Complex (immune-mediated/lymphoproliferative)
  • Key related entities: unicentric Castleman disease (UCD); idiopathic MCD (iMCD; HHV-8-negative); HHV-8/KSHV-associated MCD; POEMS-associated MCD (hoffmann2024theclinicalpicture pages 1-2, fajgenbaum2017internationalevidencebasedconsensus pages 1-4)
  • MONDO identifiers (available):
  • Castleman disease: MONDO_0015564 (OpenTargets Search: Multicentric Castleman disease)
  • Idiopathic multicentric Castleman disease: MONDO_0035838 (OpenTargets Search: Multicentric Castleman disease)
  • ICD-10-CM: D47.Z2 (Castleman disease); effective 2016-10-01 (simpson2018epidemiologyofcastleman pages 1-4, carbone2021castlemandisease pages 1-2)
  • Data provenance note: Much contemporary MCD knowledge is aggregated from consensus criteria, systematic reviews/meta-analyses, and small cohorts/registries due to rarity; some epidemiology comes from administrative claims using ICD coding + algorithmic case definitions (mukherjee2022epidemiologyandtreatment pages 1-2, hoffmann2024theclinicalpicture pages 1-2).

1. Disease information

1.1 Concise overview (current understanding)

Castleman disease (CD) is a spectrum of rare disorders characterized by characteristic lymph node histopathology and enlarged lymph nodes; it is clinically categorized into unicentric CD (single nodal region) and multicentric CD (multiple nodal regions with systemic inflammation and organ dysfunction). MCD can be life-threatening and is heterogeneous, with major subtypes defined by HHV-8/KSHV status and associated conditions such as POEMS; iMCD denotes HHV-8-negative MCD without another identified cause (hoffmann2024theclinicalpicture pages 1-2, fajgenbaum2017internationalevidencebasedconsensus pages 1-4).

1.2 Synonyms/alternative names

  • HHV-8-associated MCD is also described as KSHV-associated MCD (Kaposi sarcoma–associated herpesvirus) (polizzotto2012clinicalmanifestationsof pages 1-2).
  • iMCD is also referred to as HHV-8-negative/idiopathic MCD (fajgenbaum2017internationalevidencebasedconsensus pages 1-4).

1.3 Subtype structure and key definitions (high-level)

Entity/subtype Core definition/driver Key diagnostic elements Typical clinical/lab features First-line therapy
UCD Localized Castleman disease involving a single enlarged lymph node region; generally less symptomatic than multicentric disease (hoffmann2024theclinicalpicture pages 1-2) Single-site lymphadenopathy; lymph node histology in the Castleman spectrum; differentiate from MCD by extent of nodal involvement on imaging (CT/PET-CT) and absence of multicentric criteria (hoffmann2024theclinicalpicture pages 1-2, fajgenbaum2018novelinsightsand pages 3-3) Often asymptomatic or mild symptoms; fewer laboratory abnormalities than MCD, though symptoms/lab abnormalities can occur in a minority and may be more pronounced in pediatric UCD (hoffmann2024theclinicalpicture pages 1-2) Primarily surgical resection in UCD (denaro2025castlemandiseaseand pages 4-6)
iMCD (HHV-8-negative/idiopathic MCD) Cytokine-driven multicentric Castleman disease with no HHV-8 infection or other identified cause; IL-6 dysregulation is a key pathogenic mechanism (fajgenbaum2017internationalevidencebasedconsensus pages 1-4, rhee2022siltuximabisassociated pages 1-2) Requires both major criteria: characteristic lymph node histopathology and enlarged lymph nodes >1 cm in at least 2 stations; plus >=2 of 11 minor criteria including >=1 laboratory abnormality; must exclude infectious, autoimmune/autoinflammatory, and malignant mimics. Recommended workup includes CBC, renal/liver function, CRP/ESR, fibrinogen, immunoglobulins/free light chains, albumin, ferritin, HIV serology, HHV-8 qPCR, EBER/LANA-1 in lymph node, IL-6/VEGF where relevant, CT or PET-CT, and organ-function assessment (hoffmann2024theclinicalpicture pages 2-3, fajgenbaum2017internationalevidencebasedconsensus pages 27-29, fajgenbaum2017internationalevidencebasedconsensus pages 1-4) Constitutional symptoms; hepatosplenomegaly; edema/anasarca/ascites/pleural effusions; anemia; thrombocytopenia or thrombocytosis; hypoalbuminemia; renal dysfunction/proteinuria; polyclonal hypergammaglobulinemia; elevated CRP/ESR; lymphocytic interstitial pneumonitis; can present with cytokine storm and multiorgan dysfunction (fajgenbaum2017internationalevidencebasedconsensus pages 27-29, fajgenbaum2017internationalevidencebasedconsensus pages 1-4, rhee2022siltuximabisassociated pages 1-2) Siltuximab (anti-IL-6) is recommended first-line/frontline for iMCD; tocilizumab is an alternative in some settings (jitaru2024siltuximabinidiopathic pages 1-2, rhee2022siltuximabisassociated pages 1-2, denaro2025castlemandiseaseand pages 4-6)
HHV-8/KSHV-associated MCD Systemic polyclonal lymphoproliferative disorder driven by HHV-8/KSHV infection, often in HIV-positive or other immunosuppressed patients; viral IL-6 contributes to hypercytokinemia (rigney2025areviewof pages 10-12, estebansampedro2025castlemansdiseaseone pages 6-7, carbone2021castlemandisease pages 4-5) No formal consensus criteria cited, but experts consider compatible systemic inflammatory syndrome plus HHV-8 evidence sufficient: lymph node biopsy with HHV-8 LANA-1-positive plasmablasts/plasmacytic features, detectable HHV-8 viremia by qPCR, HIV testing, excisional biopsy preferred, CT/PET-CT for multicentric lymphadenopathy (hoffmann2024theclinicalpicture pages 2-3, rigney2025areviewof pages 12-14, rigney2025areviewof pages 10-12) Generalized lymphadenopathy, splenomegaly/hepatosplenomegaly, effusions/edema, fever/constitutional symptoms, hypoalbuminemia, anemia, thrombocytopenia, elevated CRP, polyclonal hypergammaglobulinemia, high IL-6/IL-10/vIL-6; relapsing-remitting flares may occur (rigney2025areviewof pages 10-12, rigney2025areviewof pages 12-14) Rituximab-based therapy is first-line; antiretroviral therapy is recommended in HIV-associated disease; liposomal doxorubicin/etoposide or other chemotherapy may be added in severe disease or concurrent Kaposi sarcoma; tocilizumab has also been studied (denaro2025castlemandiseaseand pages 4-6, rigney2025areviewof pages 12-14, NCT04585893 chunk 2)
POEMS-associated MCD MCD occurring in association with POEMS syndrome/plasma cell neoplasm rather than idiopathic disease (hoffmann2024theclinicalpicture pages 1-2, fajgenbaum2017internationalevidencebasedconsensus pages 29-39) Evaluate Castleman-spectrum lymph node histology with multicentric involvement together with evidence of POEMS/plasma cell disorder; VEGF and monoclonal gammopathy assessment are relevant in workup; POEMS-associated MCD is excluded from iMCD classification (hoffmann2024theclinicalpicture pages 2-3, fajgenbaum2017internationalevidencebasedconsensus pages 29-39) Shares multicentric lymphadenopathy and inflammatory features of MCD, but occurs with POEMS manifestations and plasma cell dyscrasia/monoclonal gammopathy (hoffmann2024theclinicalpicture pages 1-2, fajgenbaum2017internationalevidencebasedconsensus pages 29-39) Treat the underlying plasma cell neoplasm/POEMS-associated disease rather than as iMCD; anti-myeloma approaches are referenced for CD subtypes linked to plasma cell disorders (hoffmann2024theclinicalpicture pages 1-2, denaro2025castlemandiseaseand pages 4-6)

Table: This table summarizes the major Castleman disease entities relevant to multicentric disease, highlighting drivers, diagnostic workup, typical features, and first-line treatment. It is useful as a compact evidence-based reference for distinguishing iMCD from HHV-8-associated and POEMS-associated forms.

2. Etiology

2.1 Disease causal factors

MCD is etiologically heterogeneous: - HHV-8/KSHV-associated MCD: driven by KSHV infection and associated hypercytokinemia; a viral IL-6 homologue (vIL-6) contributes to systemic inflammation (hoffmann2024theclinicalpicture pages 1-2, polizzotto2012clinicalmanifestationsof pages 1-2). - Idiopathic MCD (iMCD): etiology is unknown but is widely characterized as cytokine-driven (often involving IL-6 dysregulation) (fajgenbaum2017internationalevidencebasedconsensus pages 1-4, rhee2022siltuximabisassociated pages 1-2).

Direct abstract quote (iMCD definition/driver):

“Human herpesvirus-8 (HHV-8)–negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6.” (Blood, 2017-03; URL: https://doi.org/10.1182/blood-2016-10-746933) (fajgenbaum2017internationalevidencebasedconsensus pages 1-4)

2.2 Risk factors

  • HHV-8/KSHV-associated MCD often occurs in the setting of HIV infection or other immunosuppression and has been described in immunocompromised populations including transplant recipients (hoffmann2024theclinicalpicture pages 1-2, mularoni2026hhv‐8kshvinsolid pages 5-6, atamna2023preventionofoncogenic pages 1-2).
  • Transplant-related risk: in solid organ transplantation (SOT), primary HHV-8 infection post-transplant increases risk of KSHV-associated diseases (including MCD), and donor-derived transmission has been documented (atamna2023preventionofoncogenic pages 1-2, mularoni2026hhv‐8kshvinsolid pages 5-6).

2.3 Protective factors / gene–environment interactions

  • No well-established protective genetic variants or gene–environment interactions were identified in the retrieved evidence; current literature emphasizes heterogeneity and incomplete understanding, especially for iMCD (fajgenbaum2017internationalevidencebasedconsensus pages 1-4).

3. Phenotypes (clinical + laboratory) with ontology suggestions

3.1 Core phenotype domains (from consensus criteria and meta-analysis)

The iMCD international consensus criteria provide a structured phenotype set (major criteria + minor criteria), which also describes common MCD clinical/lab manifestations (fajgenbaum2017internationalevidencebasedconsensus pages 27-29, fajgenbaum2017internationalevidencebasedconsensus pages 1-4).

Major phenotype anchors (diagnostic “major criteria” for iMCD)

  • Multicentric lymphadenopathy (enlarged nodes >1 cm in ≥2 nodal stations) (fajgenbaum2017internationalevidencebasedconsensus pages 27-29)
  • Characteristic lymph node histopathology within the iMCD spectrum (hypervascular/plasmacytic/mixed) (fajgenbaum2017internationalevidencebasedconsensus pages 27-29)

Minor clinical phenotypes (HPO suggestions)

From the iMCD consensus criteria (fajgenbaum2017internationalevidencebasedconsensus pages 27-29, fajgenbaum2017internationalevidencebasedconsensus pages 1-4): - Constitutional symptoms (“B symptoms”): fever, night sweats, weight loss, fatigue - HPO: Fever (HP:0001945), Night sweats (HP:0030166), Weight loss (HP:0001824), Fatigue (HP:0012378) - Organomegaly: splenomegaly/hepatomegaly - HPO: Splenomegaly (HP:0001744), Hepatomegaly (HP:0002240) - Fluid accumulation: edema/anasarca/ascites/pleural effusion - HPO: Edema (HP:0000969), Anasarca (HP:0007430), Ascites (HP:0001541), Pleural effusion (HP:0002202) - Pulmonary involvement: lymphocytic interstitial pneumonitis - HPO: Interstitial lung disease (HP:0006530) (used as a pragmatic mapping) - Cutaneous vascular lesions: eruptive cherry hemangiomatosis / violaceous papules - HPO: Hemangioma (HP:0001028), Violaceous skin discoloration (no exact single HPO term; may map to Purpura HP:0000979 depending on clinical description)

Minor laboratory phenotypes (HPO suggestions)

From the iMCD consensus criteria (fajgenbaum2017internationalevidencebasedconsensus pages 27-29): - Elevated CRP/ESR - HPO: Elevated C-reactive protein level (HP:0011227), Elevated erythrocyte sedimentation rate (HP:0003565) - Anemia - HPO: Anemia (HP:0001903) - Thrombocytopenia or thrombocytosis - HPO: Thrombocytopenia (HP:0001873), Thrombocytosis (HP:0001894) - Hypoalbuminemia - HPO: Hypoalbuminemia (HP:0003073) - Renal dysfunction / proteinuria - HPO: Proteinuria (HP:0000093), Renal insufficiency (HP:0000083) - Polyclonal hypergammaglobulinemia - HPO: Hypergammaglobulinemia (HP:0004313)

3.2 Frequency data (recent, quantitative)

A 2024 systematic review/meta-analysis (32 studies; 559 UCD, 1023 iMCD, 416 HHV8+ MCD) estimated frequencies of criteria-level features and compared iMCD vs HHV8+ MCD (Blood Advances; published online 2024-07-10; URL: https://doi.org/10.1182/bloodadvances.2024013548): - Constitutional symptoms: iMCD 46.6% vs HHV8+ MCD 98.6% (P=.038) (hoffmann2024theclinicalpicture pages 1-2) - Splenomegaly: iMCD 48.2% vs HHV8+ MCD 89.2% (P=.031) (hoffmann2024theclinicalpicture pages 1-2) - Renal dysfunction: iMCD 36.9% vs HHV8+ MCD 17.4% (P=.04 before adjustment) (hoffmann2024theclinicalpicture pages 1-2)

4. Genetic / molecular information

4.1 Causal genes (germline) and inherited forms

  • No established Mendelian causal gene is supported by the retrieved evidence for iMCD as a primary genetic disorder. Current frameworks emphasize cytokine dysregulation and exclusion of mimics rather than a defined germline etiology (fajgenbaum2017internationalevidencebasedconsensus pages 1-4).

4.2 Somatic genetics and clonality (especially relevant to HHV-8 MCD and transformation)

  • HHV-8/KSHV-associated MCD is typically a polyclonal lymphoproliferation, but it can occur alongside focal clonal proliferations (“microlymphoma”) and is associated with risk of progression to HHV-8+ lymphomas (carbone2021castlemandisease pages 4-5, rigney2025areviewof pages 10-12).
  • A 2024 molecular case report of HHV8-associated MCD with microlymphoma documented:
  • Somatically hypermutated monoclonal IGH rearrangement representing ~4% of the B-cell population in the lymph node, and also detected in bone marrow (rogges2024molecularfeaturesof pages 1-2, rogges2024molecularfeaturesof pages 5-6).
  • A pathogenic KMT2D frameshift variant plus additional VUS in KMT2D, FOXO1, ARID1A, KMT2A (rogges2024molecularfeaturesof pages 1-2, rogges2024molecularfeaturesof pages 5-6).
  • Interpretation that HHV-8 alone is insufficient for transformation (“additional genetic events” likely required), consistent with the notion that clonal progression is a key step in lymphomagenesis (rogges2024molecularfeaturesof pages 6-7).

5. Environmental information

5.1 Infectious agents

  • HHV-8/KSHV is a causal infectious agent for a major MCD subtype (KSHV–MCD). The clinical presentation is dominated by systemic inflammatory symptoms and laboratory abnormalities, with infected plasmacytoid cells in lymph nodes and elevated peripheral blood viral loads (polizzotto2012clinicalmanifestationsof pages 1-2).

6. Mechanism / pathophysiology

6.1 Causal chain (overview)

  1. Upstream triggers differ by subtype:
  2. KSHV–MCD: KSHV infection of B-cell lineage populations with lytic activation in a subset; expression of viral products including vIL-6; elevated KSHV viral loads in peripheral blood (polizzotto2012clinicalmanifestationsof pages 1-2).
  3. iMCD: unknown upstream trigger(s); consensus view is a cytokine storm with IL-6 often involved (fajgenbaum2017internationalevidencebasedconsensus pages 1-4).
  4. Intermediate mechanisms: hypercytokinemia (IL-6, and in KSHV–MCD also vIL-6; often IL-10) leading to acute-phase response, cytopenias, vascular permeability/edema, and immune-cell activation (fajgenbaum2017internationalevidencebasedconsensus pages 1-4, polizzotto2012clinicalmanifestationsof pages 1-2, rigney2025areviewof pages 10-12).
  5. Downstream clinical manifestations: constitutional symptoms, organomegaly, effusions/anasarca, organ dysfunction (kidney, lung), and risk of critical illness (cytokine storm phenotype) (fajgenbaum2017internationalevidencebasedconsensus pages 27-29, rhee2022siltuximabisassociated pages 1-2).

6.2 Key molecular pathways (with ontology suggestions)

  • IL-6 signaling (core):
  • GO: interleukin-6-mediated signaling pathway (GO:0070102)
  • JAK/STAT (noted as activated in MCD-related cytokine signaling; also cited in broader MCD pathway summaries) (denaro2025castlemandiseaseand pages 4-6, lossos2024idiopathicmulticentriccastleman pages 1-2).
  • GO: JAK-STAT cascade (GO:0007259)
  • PI3K/AKT/mTOR (highlighted particularly in some mechanistic summaries and in iMCD-TAFRO biomarker work) (denaro2025castlemandiseaseand pages 4-6, lossos2024idiopathicmulticentriccastleman pages 1-2).
  • GO: TOR signaling (GO:0031929)

6.3 Cell types involved (CL suggestions)

  • B cells / plasmablast-lineage cells (especially in KSHV–MCD):
  • CL: B cell (CL:0000236), plasmablast (CL:0000980)
  • Follicular dendritic cells (histologic emphasis in iMCD spectrum):
  • CL: follicular dendritic cell (CL:0000449)

6.4 Recent mechanistic development (2024): iMCD-TAFRO endotheliopathy, immunothrombosis, and mTOR activation

A 2024 report identified candidate mechanistic biomarkers and processes in iMCD-TAFRO, including: - Marked elevation of SVEP1 (~15-fold vs controls), proposed as an mTOR activator; SVEP1 biology connects to PI3K/AKT/mTOR signaling in vascular cells and platelets (Blood Vessels, Thrombosis & Hemostasis; 2024-06; URL: https://doi.org/10.1016/j.bvth.2024.100006) (lossos2024idiopathicmulticentriccastleman pages 1-2, lossos2024idiopathicmulticentriccastleman pages 2-3). - Immunothrombosis/endotheliopathy signatures, including microparticles expressing functional tissue factor, endothelial injury markers, complement activation, and endothelial activation markers (lossos2024idiopathicmulticentriccastleman pages 1-2). - The authors explicitly conclude: “The findings suggest that immunothrombosis plays a role in iMCD-TAFRO.” (lossos2024idiopathicmulticentriccastleman pages 2-3).

7. Anatomical structures affected

7.1 Organ level (UBERON suggestions)

  • Lymph nodes (UBERON:0000029) — central disease tissue (major diagnostic criterion in iMCD) (fajgenbaum2017internationalevidencebasedconsensus pages 27-29).
  • Spleen (UBERON:0002106) and liver (UBERON:0002107) — organomegaly is a minor criterion; splenomegaly differs by subtype frequency (hoffmann2024theclinicalpicture pages 1-2, fajgenbaum2017internationalevidencebasedconsensus pages 27-29).
  • Kidney (UBERON:0002113) — renal dysfunction/proteinuria is a minor criterion and differs in frequency between iMCD and HHV8+ MCD (hoffmann2024theclinicalpicture pages 1-2, fajgenbaum2017internationalevidencebasedconsensus pages 27-29).
  • Lung (UBERON:0002048) — lymphocytic interstitial pneumonitis is a minor criterion (fajgenbaum2017internationalevidencebasedconsensus pages 27-29).

7.2 Tissue/cell level

  • Lymph node microanatomy with germinal center regression/hyperplasia, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis in iMCD spectrum (fajgenbaum2017internationalevidencebasedconsensus pages 27-29).

8. Temporal development

8.1 Onset and course

  • iMCD may be episodic or progressive and can range from mild to acute multiorgan dysfunction requiring intensive care; this is highlighted in analyses of iMCD heterogeneity and the siltuximab trial population characterization (rhee2022siltuximabisassociated pages 1-2).
  • KSHV/HHV8-associated MCD can have a relapsing–remitting course with flares correlating with hypercytokinemia and viral load (rigney2025areviewof pages 10-12).

9. Inheritance and population

9.1 Epidemiology (statistics)

Because of rarity and coding changes, incidence estimates vary by method: - iMCD incidence and prevalence from US claims algorithm (MarketScan; 2017–2018): - Incidence: 3.4 per million/year (95% CI 1.4–9.2) - Prevalence: 6.9 per million (95% CI 3.7–13.3) - Treatment patterns: 39% corticosteroid monotherapy; 33.1% no iMCD-directed treatment; 9.8% IL-6–targeted therapy; siltuximab used in 8.7% despite being the only FDA-approved therapy (Blood Advances; 2022-01; URL: https://doi.org/10.1182/bloodadvances.2021004441) (mukherjee2022epidemiologyandtreatment pages 1-2). - Castleman disease overall incidence estimates (older claims-based work; limitations emphasized): 21–25 per million person-years with extrapolated US case counts; this work predates or is complicated by the introduction of disease-specific coding and consensus criteria (simpson2018epidemiologyofcastleman pages 1-4).

10. Diagnostics

10.1 Standardized diagnostic criteria (iMCD)

The 2017 international consensus diagnostic criteria for iMCD require: - Both major criteria (histopathology + multicentric lymphadenopathy) - ≥2 of 11 minor criteria, including ≥1 laboratory abnormality - Exclusion of infection-associated, autoimmune/autoinflammatory, and malignant mimics (Blood; 2017-03; URL: https://doi.org/10.1182/blood-2016-10-746933) (fajgenbaum2017internationalevidencebasedconsensus pages 27-29, fajgenbaum2017internationalevidencebasedconsensus pages 1-4).

Direct abstract quote (criteria structure):

“The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD.” (fajgenbaum2017internationalevidencebasedconsensus pages 1-4)

10.2 Diagnostic workup and tests (real-world implementation)

A practical workup commonly includes inflammatory markers and organ function tests, virologic testing for HIV/HHV-8, and imaging (CT/PET-CT) plus excisional biopsy (hoffmann2024theclinicalpicture pages 2-3, denaro2025castlemandiseaseand pages 4-6).

Visual evidence (tables): The following images show a recommended diagnostic workup and the iMCD consensus criteria as reproduced in a 2024 systematic review/meta-analysis (hoffmann2024theclinicalpicture media 2c791a41, hoffmann2024theclinicalpicture media 375d262e).

10.3 Biomarkers

  • CRP/ESR: part of iMCD minor criteria; CRP tracking is recommended (fajgenbaum2017internationalevidencebasedconsensus pages 27-29, fajgenbaum2017internationalevidencebasedconsensus pages 12-16).
  • IL-6 and VEGF: included in diagnostic workup summaries (cytokine profile) and are often measured clinically; VEGF is especially relevant when evaluating POEMS overlap (hoffmann2024theclinicalpicture pages 2-3).
  • HHV-8 testing in suspected MCD: HHV-8 qPCR (blood) and lymph node immunohistochemistry for LANA-1 are used to classify HHV-8-associated MCD vs iMCD (hoffmann2024theclinicalpicture pages 2-3, ohemengdapaah2024theenigmaof pages 4-5).

10.4 Differential diagnosis (must-exclude conditions)

Consensus exclusion categories include (examples): infections such as HHV-8 and other uncontrolled infections; autoimmune diseases such as SLE/RA; malignancies including lymphoma and myeloma; and POEMS syndrome (fajgenbaum2017internationalevidencebasedconsensus pages 27-29, fajgenbaum2017internationalevidencebasedconsensus pages 29-39).

11. Outcomes / prognosis

11.1 Survival and mortality (statistics)

  • A 2022 analysis of the randomized trial dataset reiterates historical poor outcomes: “35% of patients with iMCD die within 5 years of diagnosis, and 60% die within 10 years.” (Blood Advances; 2022-08; URL: https://doi.org/10.1182/bloodadvances.2022007112) (rhee2022siltuximabisassociated pages 1-2).
  • A 2024 real-world European iMCD cohort (n=48) treated with siltuximab reported:
  • Overall response rate (ORR): 71.1% (55.3% complete response; 15.8% partial response)
  • Estimated 3-year overall survival: 74%
  • Median survival: 123 months (J Hematol; 2024-10-21 online; URL: https://doi.org/10.14740/jh1343) (jitaru2024siltuximabinidiopathic pages 1-2).
  • For HHV-8-associated MCD, modern rituximab-era survival has improved substantially; a review summary reports 5-year survival ~90–92% with rituximab plus ART (rigney2025areviewof pages 12-14).

11.2 Complications

  • Organ dysfunction is part of core disease definition and criteria (renal dysfunction/proteinuria; pulmonary involvement; effusions/anasarca) (fajgenbaum2017internationalevidencebasedconsensus pages 27-29).
  • Transformation risk: HHV-8-associated MCD lesions are typically polyclonal, but monoclonal transformation (HHV-8+ DLBCL) can occur (rigney2025areviewof pages 10-12, rogges2024molecularfeaturesof pages 1-2).

12. Treatment

12.1 Pharmacotherapy (current standard practice)

  • iMCD first-line targeted therapy: siltuximab (anti–IL-6 monoclonal antibody) is recommended frontline and is supported by randomized trial evidence and real-world studies (jitaru2024siltuximabinidiopathic pages 1-2, rhee2014siltuximabformulticentric pages 1-2).
  • Randomized trial (Lancet Oncology; 2014-07-18 online; URL: https://doi.org/10.1016/S1470-2045(14)70319-5): durable tumor + symptomatic responses 34% (18/53) in siltuximab vs 0% in placebo (rhee2014siltuximabformulticentric pages 1-2).
  • Post hoc trial analysis (Blood Advances; 2022-08; URL: https://doi.org/10.1182/bloodadvances.2022007112): PFS significantly improved; median PFS 14.5 months (placebo) vs not reached (siltuximab) (rhee2022siltuximabisassociated pages 1-2).
  • HHV-8/KSHV-associated MCD: rituximab-based therapy is widely regarded as first-line; ART is recommended when HIV-associated; chemo may be added for severe disease or concurrent Kaposi sarcoma (rigney2025areviewof pages 12-14, denaro2025castlemandiseaseand pages 4-6).

12.2 Emerging/experimental and trials (real-world implementation)

Representative clinical trials from ClinicalTrials.gov include: - Ruxolitinib (JAK inhibitor) for anti–IL-6–refractory iMCD: NCT07085039 (Phase 2; open-label; recruiting; start 2025-12-18). Primary endpoint: Clinical Benefit Response at 12 months (NCT07085039 chunk 1). - Sirolimus (mTOR inhibitor) for anti–IL-6–refractory iMCD: NCT03933904 (University of Pennsylvania; for patients failed/refractory/relapsed/intolerant to anti–IL-6/IL-6R therapy) (NCT03933904 chunk 2). - Tocilizumab for KSHV-associated MCD: NCT01441063 (completed; identified in trial list) (ha2023arepatientswith pages 2-4). - Rituximab-based management in Malawi for KSHV-associated MCD: NCT04585893 includes response definitions, safety, PROMIS Global-10 QoL, and labs (CRP, KSHV viral load) with follow-up to 24 months (NCT04585893 chunk 2).

12.3 Treatment outcome data (recent statistics)

  • Real-world iMCD siltuximab outcomes (Greece/Romania; 2017–2022; follow-up through Oct 2023): ORR 71.1%, CR 55.3%, PR 15.8% (jitaru2024siltuximabinidiopathic pages 1-2).

12.4 MAXO suggestions (treatment action ontology)

  • Anti–IL-6 monoclonal antibody therapy (siltuximab) — MAXO: monoclonal antibody therapy (general mapping)
  • Anti-CD20 therapy (rituximab)
  • mTOR inhibitor therapy (sirolimus)
  • JAK inhibitor therapy (ruxolitinib)
  • Antiretroviral therapy (HIV-associated disease)

13. Prevention

13.1 Primary prevention

  • No established primary prevention for iMCD given unknown etiology (fajgenbaum2017internationalevidencebasedconsensus pages 1-4).
  • For HHV-8/KSHV-associated disease, primary prevention could theoretically include KSHV vaccination, but this remains investigational.
  • Vaccine landscape (NPJ Vaccines; 2022-09; URL: https://doi.org/10.1038/s41541-022-00535-4): workshop consensus that KSHV is “potentially vaccine-preventable,” but “no well-developed KSHV vaccine candidates” currently exist in the excerpted evidence (casper2022kshv(hhv8)vaccine pages 1-2).

13.2 Secondary/tertiary prevention (monitoring and risk mitigation in immunosuppressed populations)

  • Solid organ transplant setting (2023 review): AST guidance gives a weak recommendation for donor/recipient serologic screening in endemic regions, and targeted screening in non-endemic regions for higher-risk groups (e.g., MSM, people with HIV, injection drug users, immigrants from endemic countries). Practical barriers include lack of standardized assays and limited management algorithms (Transplant International; 2023-11; URL: https://doi.org/10.3389/ti.2023.11856) (atamna2023preventionofoncogenic pages 1-2).
  • SOT outcome observations: severe disease treated only with immunosuppression tapering had poor outcomes, while milder disease treated with rituximab/antivirals/chemotherapy had better survival; switching to mTOR inhibitors is noted to help resolve KSHV-related lesions in transplant recipients (mularoni2026hhv‐8kshvinsolid pages 5-6).

14. Other species / natural disease

  • No naturally occurring veterinary analogue of MCD was identified in the retrieved evidence.

15. Model organisms

  • The retrieved evidence set did not include full-text excerpts with direct experimental details of specific MCD animal models (e.g., vIL-6 transgenic mice) sufficient for citation here; therefore, no model organism claims are made in this report.

Expert opinion and analysis (integrated)

  1. The single most important clinical step is correct subtype classification, because iMCD and KSHV–MCD have different primary drivers (idiopathic cytokine storm vs viral-driven hypercytokinemia) and therefore different first-line therapies (anti–IL-6 vs anti-CD20/viral management) (fajgenbaum2017internationalevidencebasedconsensus pages 1-4, rigney2025areviewof pages 12-14, denaro2025castlemandiseaseand pages 4-6).
  2. Diagnostic certainty depends on combining histopathology with clinical/laboratory context and explicit exclusion of mimics. Consensus iMCD criteria were developed explicitly to solve the historical problem that “no standard diagnostic criteria or diagnostic biomarkers currently exist” and because of overlap with malignancy/infection/autoimmunity (fajgenbaum2017internationalevidencebasedconsensus pages 1-4).
  3. Recent mechanistic work in iMCD-TAFRO suggests a vascular/inflammatory thrombosis axis (endotheliopathy, tissue factor, complement activation) with an mTOR-activating signal (SVEP1), providing a rational bridge from biology to use of mTOR inhibitors in refractory disease and motivating targeted trials (lossos2024idiopathicmulticentriccastleman pages 1-2, NCT03933904 chunk 2).

Key URLs (selected)

  • iMCD consensus diagnostic criteria (Blood, 2017-03): https://doi.org/10.1182/blood-2016-10-746933 (fajgenbaum2017internationalevidencebasedconsensus pages 1-4)
  • Systematic review/meta-analysis of CD clinical picture (Blood Advances, 2024-09 issue; online 2024-07-10): https://doi.org/10.1182/bloodadvances.2024013548 (hoffmann2024theclinicalpicture pages 1-2)
  • Siltuximab RCT (Lancet Oncology, 2014-07-18 online): https://doi.org/10.1016/S1470-2045(14)70319-5 (rhee2014siltuximabformulticentric pages 1-2)
  • Real-world iMCD siltuximab cohort (J Hematol, 2024-10-21 online): https://doi.org/10.14740/jh1343 (jitaru2024siltuximabinidiopathic pages 1-2)
  • iMCD-TAFRO SVEP1/tissue factor/endotheliopathy (Blood Vessels Thromb Hemost, 2024-06): https://doi.org/10.1016/j.bvth.2024.100006 (lossos2024idiopathicmulticentriccastleman pages 1-2)
  • HHV-8 prevention in transplant recipients (Transplant International, 2023-11): https://doi.org/10.3389/ti.2023.11856 (atamna2023preventionofoncogenic pages 1-2)
  • KSHV vaccine perspective (NPJ Vaccines, 2022-09): https://doi.org/10.1038/s41541-022-00535-4 (casper2022kshv(hhv8)vaccine pages 1-2)

Evidence gaps / not available in retrieved sources

  • Orphanet/MeSH identifiers were not directly retrievable from the current evidence excerpts; MONDO and ICD-10-CM identifiers are provided where supported (OpenTargets Search: Multicentric Castleman disease, simpson2018epidemiologyofcastleman pages 1-4).
  • Model organism evidence for MCD-like disease (e.g., vIL-6 transgenic mice) was not available as citeable excerpted text in this run.
  • Large prospective registries and 2023–2024 iMCD refractory-therapy cohorts (e.g., sirolimus retrospective series) were not available as full-text evidence in the retrieved context; only trial registry entries and mechanistic reports could be cited.

References

  1. (hoffmann2024theclinicalpicture pages 1-2): Christian Hoffmann, Eric Oksenhendler, Sarah Littler, Lisa Grant, Karan Kanhai, and David C. Fajgenbaum. The clinical picture of castleman disease: a systematic review and meta-analysis. Blood Advances, 8:4924-4935, Sep 2024. URL: https://doi.org/10.1182/bloodadvances.2024013548, doi:10.1182/bloodadvances.2024013548. This article has 28 citations and is from a peer-reviewed journal.

  2. (fajgenbaum2017internationalevidencebasedconsensus pages 1-4): David C. Fajgenbaum, Thomas S. Uldrick, Adam Bagg, Dale Frank, David Wu, Gordan Srkalovic, David Simpson, Amy Y. Liu, David Menke, Shanmuganathan Chandrakasan, Mary Jo Lechowicz, Raymond S. M. Wong, Sheila Pierson, Michele Paessler, Jean-François Rossi, Makoto Ide, Jason Ruth, Michael Croglio, Alexander Suarez, Vera Krymskaya, Amy Chadburn, Gisele Colleoni, Sunita Nasta, Raj Jayanthan, Christopher S. Nabel, Corey Casper, Angela Dispenzieri, Alexander Fosså, Dermot Kelleher, Razelle Kurzrock, Peter Voorhees, Ahmet Dogan, Kazuyuki Yoshizaki, Frits van Rhee, Eric Oksenhendler, Elaine S. Jaffe, Kojo S. J. Elenitoba-Johnson, and Megan S. Lim. International, evidence-based consensus diagnostic criteria for hhv-8-negative/idiopathic multicentric castleman disease. Blood, 129 12:1646-1657, Mar 2017. URL: https://doi.org/10.1182/blood-2016-10-746933, doi:10.1182/blood-2016-10-746933. This article has 753 citations and is from a highest quality peer-reviewed journal.

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