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)

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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

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TACI and CSR
Macpherson AJ et al. 2002. BlySsful interactions
between DCs and B cells. Nature Immunology.
3(9)298-800.
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Thymus-dependent B cell activation
Middletons Allergy. 6th Edition.
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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.
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Work-up

• Serum immunoglobulins
• lt2 SD below mean for age
• Immunize
• Pneumovax
• Tetanus toxoid
• Hib
• Check pre- and post-immunization titers

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Treatment

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

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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

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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

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Signs and symptoms (contd)

• Can also present with associated paraneopolastic
  syndrome
• Most clinically important syndromes are
  myasthenia gravis, pure red cell aplasia and
  hypogammaglobulinemia

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Paraneoplastic syndromes
UpToDate. 2006. Clinical presentation and
management of thymomas.
23
Diagnosis

• Imaging
• CXR
• CT
• MRI
• PET
• Biopsy

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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
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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

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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

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Unclear pathogenesis

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

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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

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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
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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

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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