CVID and Good’s Syndrome: Causes of Hypogammaglobulinemia Pierre Yong, MD October 16, 2006
Causes of recurrent pulmonary infections • CVID • Good’s syndrome • Immotile cilia syndrome • Cystic fibrosis • Obstruction • Leukocyte adhesion defects • Neutropenia
CVID • Hypogammaglobulinemia • Recurrent sinopulmonary infections • Poor B cell response to immunizations • Variable T cell defects
Clinical manifestations • Infections • Sinopulmonary • Meningitis • Sepsis • Encapsulated organisms • Enterovirus
Infections (con’td) Cunningham-Rundles C, Bodian C. 1999. CVID: clinical and immunological features of 248 patients. Clin Immunol. 92(1):34-48.
Clinical manifestations (con’td) • Bronchiectasis • GI • Diarrhea • Giardiasis • Granulomatous disease • AI disease • AIHA • ITP
Clinical manifestations (con’td) • Malignancy • Lymphoma • Gastric CA
Pathogenesis • Unknown
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.
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)
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.
TNF receptor superfamily http://www.medscape.com/viewarticle/516193_print
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
TACI and CSR Macpherson AJ et al. 2002. BlySsful interactions between DCs and B cells. Nature Immunology. 3(9):298-800.
Thymus-dependent B cell activation Middleton’s Allergy. 6th Edition.
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. 354;18:1901-12.
Work-up • Serum immunoglobulins • <2 SD below mean for age • Immunize • Pneumovax • Tetanus toxoid • Hib • Check pre- and post-immunization titers
Treatment • IVIG • 400-500 mg/kg q4-5 wks • Antibiotics
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
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
Signs and symptoms (con’td) • Can also present with associated paraneopolastic syndrome • Most clinically important syndromes are myasthenia gravis, pure red cell aplasia and hypogammaglobulinemia
Paraneoplastic syndromes UpToDate. 2006. Clinical presentation and management of thymomas.
Diagnosis • Imaging • CXR • CT • MRI • PET • Biopsy
WHO Classification Reidel RF et al. 2006. Thymoma: benign appearance, malignant potential. Oncologist. 11:887-894.
Good’s 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. 26:1-19.
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
Signs and symptoms • Recurrent sinopulmonary infections with encapsulated organisms • Bacterial UTIs and skin infections • Arthritis • Opportunistic infections with viruses and fungi • Diarrhea (25-35%)
Infections Tarr PE et al. 2001. Infections in patients with immunodeficiency with thymoma (Good Syndrome). Medicine. 80:123-133.
Work-up • B cell defect • Few or absent B cells • Decreased quantitative immunoglobulins • T cell defect • Lymphopenia • CD4+ lymphopenia • Reversal of CD4:CD8 ratio • Impaired T cell response to mitogens Kellkher P et al. 2003. What is Good’s syndrome? Immunological abnormalities in patients with thymoma. J Clin Path. 56:12-16.
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. 9:49-52.
Unusual case (cont’d) • 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
Unclear pathogenesis • Cytokine secreted from bone marrow stromal cells • Autoantibodies • T cells directly or indirectly inhibit B cells
Thymoma: Masoaka staging system Treatment Reidel RF et al. 2006. Thymoma: benign appearance, malignant potential. Oncologist. 11:887-894.
Treatment (con’td) • Thymoma • Resection • Radiation • Chemotherapy • Hypogammaglobulinemia • IVIG • Tend not to improve after resection of thymoma
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 • Good’s syndrome = thymoma + hypogammaglobulinemia
Summary (con’td) • All patients with thymoma and any infections should be evaluated for possible hypogammaglobulinemia • Treatment for Good’s syndrome is Ig replacement and thymoma resection