Malignancy  NHL 7.7% - mostly extranodal, all B cell type  Others - –Waldenstrom’s macroglobulinemia –Hodgkin’s disease –Adenocarcinoma - stomach, ovary, colon –Sq cell Ca - vagina, skin, mouth, lung –Ca - breast, prostate –Melanoma Cunningham-Rundes and Bodian (Clin Immunol 1999; 92:34-48)

GI Diseases (n=248) Nodular lymphoid hyperplasia10 Malabsorption, no other diag.10 Giardiasis 8 UC 4 Ulc. Proctitis 3 Crohn’s disease 9 Malnutrition needing TPN 5 Campylobacter enteritis 5 Cunningham-Rundes and Bodian (Clin Immunol 1999; 92:34-48)

Granulomatous disease  20% patients  Lung, lymph nodes, skin, bone marrow, and liver  Histology: non-caseating granuloma, indistinguishable from sarcoidosis  Asymptomatic/ dyspnea if lung involvement/anemia or thrombocytopenia if hypersplenism  Corticosteroid : effectively in some but increased risk of infection  Splenectomy

Laboratory Abnormalities   IgG, mostly with  IgA and IgM  Lymphopenia 20%  B cell numbers - mostly normal   CD4/CD8 ratios,  in CD4+CD45+ T cells  Low or absent isohemagglutinin titers and specific Ab levels  T cell in vitro proliferation : subnormal in 50% to mitogen, antigens

Primary immunodeficiency syndrome X-linked agammaglobulinemia Transient hypogammaglobulinemia of infancy Infectious agents CMV, EBV, HIV Malignancy Lymphoma, multiple myeloma, CLL Protein-losing states Nephrotic syndrome, Protein-losing enteropathy Drugs Cyclophosphamide, phenytoin, Gold, Penicillamine Differential diagnosis

XLA CVIDTHI Mutation of gene Btk -- Family HxX-linked -- OnsetLate 1 st yearAny age1 st year Recovery y/o Lymph nodesmallhyperplasia -- B cell umberabsencenear normalnormal T cellnormalsubtle normal Ig IgG ↓ IgA ↓ IgM ↓ IgG ↓ IgA ↓ IgM ↓ IgG ↓ IgA ↓ IgM  or normal

Treatment  Early and aggressive antibiotic therapy,  Replacement with IVIG: 400 mg/kg/month  Ongoing therapy for autoimmune and inflammatory disorders & surveillance for malignancy

IVIG  Trough levels > 350 mg/dL without infection  Levels > 500 mg/dL if severe infection persists  Back or abdominal pain, nausea, vomiting, chills, fever, and myalgia -> nonanaphylactic binding of infused Abs to microbial Ag  True anaphylactic reactions : rare flushing, facial swelling, dyspnea, hypotension anti-IgA antibodies (IgE isotype)

IVIG  Receive very low IgA product is completely IgA deficient  Risk of infection : HIV : no risk HCV : more severe course in CVID patients

Treatment IL-2  15 patients received PEG-IL mo / 29 control   T cell proliferative response to mitogen   T cell proliferative response to antigen (candida and tetanus)   Antibody response to immunization with neoantigen bacteriophage  X 174   Days of bronchitis, diarrhea and joint pain Clin Immunol 2001;100(2) :181-90

Treatment  Retinoic acid Decreased vitamin A level in CVID patients Associated with chronic bacterial infection and splenomegaly Supplementation :  IL-10,  TNF-  in vivo:  IgA,  mitiogen response to PHA  Cimetidine ?  IL-10 ? Eur J Clin Invest 2000;30(3) :252-9

Mortality and Survival  248 patients; median follow-up 7 yrs (0-25)  57 died from 1-32 yrs after diagnosis, ages yrs (median age 43) - 27%  Causes -Lymphoma, cor pulmonale, hepatitis, malnutrition, other malignancies, vasculitis, etc.  Poor prognostic signs: % of peripheral B cells, initial IgG level  For each %  in B cell numbers, risk of death on follow-up  by a factor of 0.92 Cunningham-Rundes and Bodian (Clin Immunol 1999; 92:34-48)