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CVID and Good

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CVID and Good s Syndrome: Causes of Hypogammaglobulinemia Pierre Yong, MD October 16, 2006 Causes of recurrent pulmonary infections CVID Good s syndrome Immotile ... – PowerPoint PPT presentation

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Title: CVID and Good


1
CVID and Goods Syndrome Causes of
Hypogammaglobulinemia
  • Pierre Yong, MD
  • October 16, 2006

2
Causes of recurrent pulmonary infections
  • CVID
  • Goods syndrome
  • Immotile cilia syndrome
  • Cystic fibrosis
  • Obstruction
  • Leukocyte adhesion defects
  • Neutropenia

3
CVID
  • Hypogammaglobulinemia
  • Recurrent sinopulmonary infections
  • Poor B cell response to immunizations
  • Variable T cell defects

4
Clinical manifestations
  • Infections
  • Sinopulmonary
  • Meningitis
  • Sepsis
  • Encapsulated organisms
  • Enterovirus

5
Infections (contd)
Cunningham-Rundles C, Bodian C. 1999. CVID
clinical and immunological features of 248
patients. Clin Immunol. 92(1)34-48.
6
Clinical manifestations (contd)
  • Bronchiectasis
  • GI
  • Diarrhea
  • Giardiasis
  • Granulomatous disease
  • AI disease
  • AIHA
  • ITP

7
Clinical manifestations (contd)
  • Malignancy
  • Lymphoma
  • Gastric CA

8
Pathogenesis
  • Unknown

9
Monogenetic defects
Salzer Ulrich et al. TACItly changing tunes
farewell to a yin and yang of BARR receptor and
TACI in humoral immunity? new genetic defects in
CVID. 2005. Curr Opin Allergy Clin Immunol.
5(6)496-503.
10
ICOS
  • Inducible co-stimulator of activated T cells
  • Expressed only on activated T cells
  • ICOS-ICOS ligand interaction is important for
    terminal B cell differentiation into memory cells
    and plasma cells
  • Homozygous deficiency (AR)

11
ICOS in CVID Patients
Grimbacker B et al. Homozygous loss of ICOS is
associated with adult-onset common variable
immunodeficiency. 2003. Nature Immunology.
4(3)261-68.
12
TNF receptor superfamily
http//www.medscape.com/viewarticle/516193_print
13
TACI
  • Binds BAFF and APRIL
  • Impairment in T cell independent responses to
    polysaccharide antigens of encapuslated bacteria
  • Identified mutations in extracellular domain,
    transmembrane region and intracellular domain
  • AD and AR inheritance

14
TACI and CSR
Macpherson AJ et al. 2002. BlySsful interactions
between DCs and B cells. Nature Immunology.
3(9)298-800.
15
Thymus-dependent B cell activation
Middletons Allergy. 6th Edition.
16
CD19
  • CD19 is part of the CD19 complex, which signals
    with BCR, decreasing the threshold for
    receptor-dependent signaling
  • Frameshift mutations cause premature stop codons,
    resulting in deletion of cytoplasmic domain of
    CD19
  • Impaired calcium flux after stimulation of B cells

van Zelm et al. An antibody-deficiency syndrome
due to mutations in the CD19 gene. NEJM. 2006.
354181901-12.
17
Work-up
  • Serum immunoglobulins
  • lt2 SD below mean for age
  • Immunize
  • Pneumovax
  • Tetanus toxoid
  • Hib
  • Check pre- and post-immunization titers

18
Treatment
  • IVIG
  • 400-500 mg/kg q4-5 wks
  • Antibiotics

19
Thymomas
  • Neoplasm of thymic epithelial cells
  • Usually benign histology but can have aggressive
    behavior
  • Most common tumor of the anterior mediastinum
  • 90 of thymomas occur in mediastinum

20
Signs and symptoms
  • Up to ½ of patients are asymptomatic
  • Can present with local or invasive organ
    involvement
  • Cough
  • Dypsnea
  • Chest pain
  • SVC syndrome
  • Hoarseness

21
Signs and symptoms (contd)
  • Can also present with associated paraneopolastic
    syndrome
  • Most clinically important syndromes are
    myasthenia gravis, pure red cell aplasia and
    hypogammaglobulinemia

22
Paraneoplastic syndromes
UpToDate. 2006. Clinical presentation and
management of thymomas.
23
Diagnosis
  • Imaging
  • CXR
  • CT
  • MRI
  • PET
  • Biopsy

24
WHO Classification
Type Pathology 10 year survival
A Medullary 100
AB Mixed 100
B1 Predominantly cortical 83
B2 Cortical 83
B3 Well-differentiated thymic CA 36
C Thymic CA 28
Reidel RF et al. 2006. Thymoma benign
appearance, malignant potential. Oncologist.
11887-894.
25
Goods syndrome
  • Thymoma with associated hypogammaglobulinemia
  • Thymoma can precede or occur after develop of
    immunodeficiency

Good RA. 1954. Agammaglobulinemia a provocative
experiment of nature. Bull Univ Minnesota.
261-19.
26
Thymoma and Hypogammaglobulinemia
27
Epidemiology
  • Occurs in less than 5 of thymomas
  • Usually older women
  • Usually spindle cell morphology
  • Occurs in up to 10 of patients presenting with
    hypogammaglobulinemia

28
Signs and symptoms
  • Recurrent sinopulmonary infections with
    encapsulated organisms
  • Bacterial UTIs and skin infections
  • Arthritis
  • Opportunistic infections with viruses and fungi
  • Diarrhea (25-35)

29
Infections
Tarr PE et al. 2001. Infections in patients with
immunodeficiency with thymoma (Good Syndrome).
Medicine. 80123-133.
30
Work-up
  • B cell defect
  • Few or absent B cells
  • Decreased quantitative immunoglobulins
  • T cell defect
  • Lymphopenia
  • CD4 lymphopenia
  • Reversal of CD4CD8 ratio
  • Impaired T cell response to mitogens

Kellkher P et al. 2003. What is Goods syndrome?
Immunological abnormalities in patients with
thymoma. J Clin Path. 5612-16.
31
Unusual case
  • 15 year old with thymoma and chronic thrush and
    generalized HSV-2 infections
  • Normal response to T cell mitogens
  • No response to Candida antigen at initial
    evaluation but normal T cell proliferation 6
    weeks after removal of thymoma
  • Anergy panel negative 1 week after removal of
    thymoma to Tetanus toxoid 5 weeks later

Sicherer SH et al. 1998. Thymoma and cellular
immune deficiency in an adolescent. Pediatr
Allergy Immunol. 949-52.
32
Unusual case (contd)
  • Normal serum Ig levels
  • Protective levels of antibody to Hib and a
    positive rubella titer
  • Normal response after booster doses of tetanus
    and diphtheria toxoids and immunization with
    pneumococcal vaccine

33
Unclear pathogenesis
  • Cytokine secreted from bone marrow stromal cells
  • Autoantibodies
  • T cells directly or indirectly inhibit B cells

34
Treatment
  • Thymoma Masoaka staging system

Stage Criteria
I Encapsulated neoplasm
IIa Microscopic invasion
IIb Macroscopic invasion into fatty tissue
III Invasion into great vessels, pericardium, or lung
IVa Pericardial or pleural metastases
IVb Hematogenous or lymphangitic spread
Reidel RF et al. 2006. Thymoma benign
appearance, malignant potential. Oncologist.
11887-894.
35
Treatment (contd)
  • Thymoma
  • Resection
  • Radiation
  • Chemotherapy
  • Hypogammaglobulinemia
  • IVIG
  • Tend not to improve after resection of thymoma

36
CVID and Goods Syndrome
CVID Goods
Recurrent infections Yes Yes
B cell present Yes No
T cell defects Yes Yes
Low Igs Yes Yes
Treatment IVIG Resection, IVIG
37
Summary
  • CVID is the second most common PID syndrome
  • Monogenetic defects have been identified a cause
    of CVID, but the pathogenesis in the majority of
    CVID patients is unknown
  • Goods syndrome thymoma hypogammaglobulinemia

38
Summary (contd)
  • All patients with thymoma and any infections
    should be evaluated for possible
    hypogammaglobulinemia
  • Treatment for Goods syndrome is Ig replacement
    and thymoma resection
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