Anita Gewurz

Comparison of the efficacy of IGIV-C, 10% (caprylate/chromatography) and IGIV-SD, 10% as replacement therapy in primary immune deficiency ☆: A randomized double-blind trial

A novel method of large-scale chromatography has been developed to improve recovery and purity of immunoglobulin G (IgG) from pooled plasma. The current study compares safety, toxicity and efficacy of two intravenous immunoglobulin products: a novel formulation, IGIV caprylate/chromatography (IGIV-C; Gamunex, 10%) and a licensed solvent/detergent-treated product, Gamimune N, 10% (IGIV-SD). The study, a randomized, double-blind, parallel group, therapeutic equivalence trial, was conducted at 25 treatment centers in Canada and the United States. Patients (n=172) having confirmed chronic primary immunodeficiency (PID), aged 1-75 years, and receiving IGIV therapy were enrolled. For 9 months, patients were treated with IGIV-C or IGIV-SD in accordance with the patients individualized treatment regimen utilized before study entry. The primary endpoint was the proportion of patients with >or=1 validated acute sinopulmonary infection during the treatment period. Secondary endpoints included the proportion of patients with all infections, time to first infection, annual infection rates, lung function parameters, infusion-related safety and viral safety. The annual validated infection rate in the IGIV-C group was 0.18 compared to 0.43 in the IGIV-SD group (p=0.023). Nine patients receiving IGIV-C experienced validated infections, compared to 17 patients in IGIV-SD group (p=0.06). Acute sinusitis (validated plus clinically defined) was less frequent in the IGIV-C group (p=0.012). Presence of bronchiectasis did not affect efficacy. Adverse reactions were similar in frequency and severity in both groups. No evidence of viral transmission was observed. IGIV-C appears to be superior to IGIV-SD in preventing validated sinopulmonary infections, especially acute sinusitis, in patients with PID.

Assessing thymopoiesis in patients with common variable immunodeficiency as measured by T-cell receptor excision circles.

BACKGROUND Common variable immunodeficiency (CVID) is one of the most common primary immune deficiencies. The immunologic hallmark of CVID is failure of B-cell differentiation and impaired secretion of immunoglobulins. However, there is mounting evidence of accompanying T-cell dysregulation, which could be due to abnormal thymic function because the thymus plays a crucial role in T-cell development. Recently, it was shown that the human thymus remains functional well into adulthood. Current data show that the level of T-cell receptor excision circles (TRECs) correlates well with active thymopoiesis. OBJECTIVE To determine whether thymic dysfunction contributes to the pathogenesis of CVID. METHODS We evaluated 15 patients, aged 19 to 65 years, previously diagnosed as having CVID. Genomic DNA was isolated from peripheral blood mononuclear cells of each patient. Thymic output was evaluated by measuring coding joint TRECs in the total T-cell population using real-time polymerase chain reaction. RESULTS Results were compared with known age-matched reference values. The median TREC level in patients with CVID (82,034 copies/microg of DNA) was significantly higher than that in the healthy cohort (43,000 copies/microg of DNA) (P < .001). In examining the relationship between TREC levels and age, we noted that TREC levels significantly declined faster with age in patients with CVID vs the healthy cohort. CONCLUSIONS In these patients, thymic dysregulation may be a factor in CVID, with an accelerated rate of TREC loss with age compared with healthy adults.

Developing resources to teach and assess the core competencies: a collaborative approach.

Graduate medical education programs face new challenges as they seek to comply with the mandate from the Accreditation Council on Graduate Medical Education to demonstrate that they are teaching and assessing residents on the six core competencies. The authors describe a project designed as a collaborative venture between the American Academy of Allergy, Asthma, and Immunology (AAAAI) and the Center for Educational Outcomes at Dartmouth College (CEdO) to provide residency programs in allergy/immunology with resources for teaching and assessing the core competencies. The goal was to create a set of learning and assessment resources that maximized the content knowledge expertise provided by the AAAAI and the learning expertise provided by CEdO. A highly interactive, iterative process was used to create a set of Web-based modules. Bilateral communication, buy-in, and active involvement in the process were seen as crucial to the development of resources and their successful implementation. Approximately 18 months after the modules were made available to training program directors, 80% of the directors surveyed were aware of and had accessed the modules. The joint creation process used in this project, designed to be generally applicable across specialties, reveals how the burden of meeting new requirements can be decreased when experts in content knowledge and experts in learning collaborate.

744 IDENTICAL TWIN GIRLS WITH RECURRENT SEVERE INFECTIONS ASSOCIATED WITH THE ABSENCE OF THE SECOND COMPONENT OF COMPLEMENT

Deficiency of the second component of complement has frequently been reported but has only rarely been associated with severe infection. We now report identical twin girls with this defect who each have had four episodes of bacterial sepsis in the first 19 months of life; one episode was associated with meningitis in one patient. The twins have normal levels of circulating IgM, IgG, IgA, and IgE, and functional antibodies are present. There is no neutropenia or lymphopenia, and both girls have positive skin tests with more than 10 millimeters of induration to mumps and candida antigens as well as normal formazan slide tests. However, total hemolytic complement activity is undetectable, and attributable to selective and complete deficiency of C2 in each child; activity is restored with purified C2. Levels of C1q, C4, C3, CS, properdin and Factor B protein are each within normal limits, as is alternative pathway activity. These patients are similar to many others who lack C2 in that they have the Aw25, Aw33 and B18 antigens at the HL-A locus. There is no clinical evidence of a collagen disorder, but rheumatoid factor is present in a titer of 1:80 in both girls. There is a normal staphylococcal kill test but decreased ability to opsonize for phagocytosis of Candida albicans. These girls are unique in that they are identical twins with isolated C2 deficiency with a propensity to recurrent infections early in life.

Soluble copolymer of wasp venom with human albumin for venom immunotherapy

Polymerization of allergens decreases allergenicity while retaining immunogenicity, as we have demonstrated for ragweed, grass, and tree pollens. We have also polymerized bee venom with human albumin to form soluble, high-molecular-weight copolymers that are immunogenic in rabbits. We now have prepared a soluble wasp venom-albumin polymer (WVAP), molecular weight greater than or equal to 240,000 daltons, by glutaraldehyde treatment and Sephacryl S-300 column fractionation. Rabbits immunized with WVAP produced IgG to both WVAP and wasp venom (WV), as measured by ELISA. IgG against WVAP was totally inhibitable by a mixture of WV and albumin, demonstrating both retention of native antigens and absence of new antigenic determinants in WVAP. IgG against WV in serum from patients receiving maintenance doses of WV immunotherapy was inhibited by WVAP. In summary, we have synthesized a soluble, high-molecular-weight copolymer of WV that retains the immunogenicity of native WV, contains no new antigenic determinants, and has potential value in the treatment of patients with WV anaphylaxis.

Soluble copolymers of yellow jacket, yellow hornet and white faced hornet with human albumin for venom immunotherapy.

Soluble polymers have been prepared by polymerizing human serum albumin (HSA) with either yellow jacket venom (YJV), yellow hornet venom (YHV) or white faced hornet venom (WFHV). The venom-albumin polymer preparations were fractionated on Sephacryl S-300 to have a molecular weight range higher than catalase (2.4 x 10(5) daltons). Rabbits were immunized with either yellow jacket venom-albumin polymer (YJVAP), yellow hornet venom-albumin polymer (YHVAP) or white faced hornet venom-albumin polymer (WFHVAP). Rabbits immunized with venom-albumin polymer (VAP) produced IgG antibody to VAP and venom, as measured by enzyme-linked immunosorbent assay (ELISA). Experiments to demonstrate antigenic completeness and absence of new antigenic determinants in the polymer were performed using WFHVAP. IgG against WFHVAP was completely inhibited by a mixture of WFHV and HSA demonstrating the absence of new antigenic determinants in WFHVAP. IgG against WFHV in sera from patients receiving maintenance doses of WFHV immunotherapy was completely inhibited by WFHVAP, demonstrating antigenic completeness. We have previously described similar results with bee venom-albumin polymer and wasp venom-albumin polymer. We now conclude that VAP preparations of all five clinically relevant hymenoptera venoms have potential value in the treatment of hymenoptera anaphylaxis.