Aseptic meningitis following therapy with immune globulins: a combination of product features and patient characteristics?

BACKGROUND: Aseptic meningitis (AM) represents a recognized side effect of immune globulin (IG) therapy and may warrant additional diagnostic procedures and therapy with anti-infective drugs until a definite diagnosis can be established. Although, to date, only small case series have been published, the objective of the current study was to investigate a large case series of patients with AM. STUDY DESIGN AND METHODS: The pharmacovigilance safety database of a 10% liquid IG (Gammagard Liquid) was queried for all reports of AM. Patient demographics, treatment-specific data, and product-specific data were determined. The proportional reporting rates of AM were compared according to the route of administration (intravenous vs. subcutaneous) and molecular size distribution of IG lot (dimer content ≥ 8 vs. < 8%). RESULTS: In total, 144 AM episodes were reported in 136 distinct patients. Females were affected by AM nearly four times more than males. AM was not limited to patients who received high-dose IG therapies but was observed in those who received low-dose regimens in percentages comparable to the estimated usage patterns of IG. Lots that had high dimer values were associated with AM significantly more often than lots that had low dimer values (p < 0.001), and subcutaneous IG administration was associated with lower rates of AM compared with intravenous IG administration (p = 0.055). CONCLUSION: In contrast to previously published data, AM was observed in both low-dose and high-dose regimens without favoring high IG doses, and females were affected nearly four times more often than males. Immunoglobulin G dimers may play a role in the etiology of AM, and subcutaneous administration may be associated with a lower rate of AM compared with intravenous administration.

Hemolytic events associated with intravenous immune globulin therapy: a qualitative analysis of 263 cases reported to four manufacturers between 2003 and 2012.

BACKGROUND: Objectives of this study were to identify possible patient and product risk factors for intravenous immune globulin (IVIG)-associated hemolysis, a recognized side effect of IG therapy; analyze IVIG indications; and examine dose levels (g/kg body weight) and total IVIG dose administered. STUDY DESIGN AND METHODS: Reports of IVIG-associated hemolysis for 10 years (2003-2012) for four participating IG manufacturers were identified using a uniform case definition (Standardized MedDRA Query "Hemolytic disorders," Broad Scope, Version 16.0) and analyzed. RESULTS: IVIG-associated hemolysis appears to occur predominantly at dose levels exceeding 0.5 g/kg, with 72% of cases with known dose information having dose levels between 1 and 2.5, and can affect patients at any age, without a clear gender preference. No association was found between hemagglutinin exposure and development of hemolysis, nor between dose levels and odds of receiving a transfusion to treat hemolysis. Patients with blood group AB may be at higher risk of hemolysis than those with group A or B. CONCLUSION: Data examined confirm that IVIG-associated hemolysis predominantly occurs following infusion of high IVIG doses, and can affect patients at every age of both genders. While presence of hemagglutinins appears to play a major role in pathogenesis of hemolytic disorders, high hemagglutinin titers of IVIG products themselves seem to be of less relevance, indicating that the pathomechanism of IVIG-associated hemolysis may be related to the presence, but not the absolute amount, of hemagglutinins. Patients with hemolysis had additional hemolytic risks such as multiple comorbidities and medication use. IG-treated patients with multiple risks should be closely monitored for hemolysis.

Anti-A and anti-B titers in donor plasma, plasma pools, and immunoglobulin final products.

BACKGROUND: High-dose intravenous immunoglobulin (IVIG) treatments are implicated in hemolytic events in some patients receiving treatment. The passive transfer of IgG anti-A and anti-B agglutinin is thought to play a role in the development of these events. The purpose of this study was to determine the prevalence of high-titer IgG anti-A and anti-B in plasma donors and investigate if there is any advantage of excluding these donors from the donor pool to limit anti-A and anti-B content in IVIG product. STUDY DESIGN AND METHODS: IgG anti-A and anti-B levels were assessed from group O donor plasma, manufacturing IgG plasma pools, and finished IVIG product (Gammagard Liquid). Antibody level in group O donors was also assessed by sex and age for their relative contribution of antibody to the plasma pool. RESULTS: The majority of group O donors (80%) had antibody titers of less than 1000. Of those with titers of at least 1000, theoretical estimates provide further evidence that the effects of high-titer donors are minimal. Antibody levels in plasma pools both during the manufacturing process and from the final IVIG product also support that anti-A and anti-B levels are low. In general, there were more females than males with higher antibody titer levels, with significantly more females than males with anti-A. CONCLUSION: Excluding donors with high anti-A and anti-B titers has minimal impact on the finished IVIG product titers due to ABO antibody neutralization and the dilution factor in the manufacturing pool.

Hemolytic events after the administration of lyophilized versus liquid immune globulin: an analysis of a single manufacturer's safety database.

BACKGROUND: Recent publications have raised concerns that liquid immune globulins (IGs) may be associated with either a higher or a lower frequency of hemolytic events compared to lyophilized IGs, among other reasons due to the differences of their isohemagglutinin content. The aim of this study was to evaluate the relationship of hemolytic events to product presentation (liquid versus lyophilized) and to examine the relationship between total IG doses administered and the individual isohemagglutinin titers of IG lots infused. STUDY DESIGN AND METHODS: The reporting rate as well as the proportional reporting rate (PRR) of hemolytic events for liquid (Gammagard liquid [GGL]) and lyophilized IG (Gammagard S/D [GGSD]) received spontaneously from the United States was calculated. For all hemolytic events received spontaneously from global sources, total IG doses (g/kg body weight) and the loading dose of isohemagglutinins (total IG dose infused × isohemagglutinin titers of infused lots) were determined. RESULTS: With 0.27 and 0.33 cases per 1 million grams distributed, the reporting rates for GGL and GGSD are comparable, further confirmed by a PRR of 1.0 (95% confidence interval, 0.4-2.7). Hemolytic events for GGL and GGSD were observed with low loading doses of isohemagglutinins, and lots with high isohemagglutinin titers did not contribute to the development of hemolytic events in a higher proportion than lots with low titers CONCLUSIONS: Hemolysis associated with GGL or GGSD can occur even with low loading doses of isohemagglutinins. Data presented do not indicate that high isohemagglutinin titers of IG products play a major role in the development of these events.

Time-Resolved Studies of Light Propagation in Crassula and Phaseolus Leaves.

Abstract- Time-resolved transmittance was used to extract in vivo optical properties of leaves of green plants experimentally. In time-resolved transmittance measurements an ultrashort light pulse is directed onto the surface of the object and the transmitted light is measured with a time resolution in the range of picoseconds. A table-top terawatt laser was used to generate 200 fs light pulses at 790 nm with a repetition rate of 10 Hz. The light pulses were focused through a cuvette filled with water to produce white light pulses and optical filters were placed in the beam path to select the wavelength of the light focused onto the leaf surface. The time profiles of the light transmitted through the leaves was recorded with a streak camera having a time resolution of about 2.5 ps. Results from Crassula falcata and Phaseolus vulgaris studied at 550, 670 and 740 nm are reported. The three selected wavelength regions represent medium, high and a low absorption of light, respectively. A library of curves was generated using Monte Carlo simulation, and the absorption and scattering coefficients were extracted by comparison of experimental curves with this library. Our results suggest that in the case of the thin (200 µm) Phaseolus leaves and certainly in the case of the thick (4 mm) Crassula leaves, light scattering plays an important role in light transport through the leaf and should also affect light flux in these leaves.