Incidence and risk factors for intravenous immunoglobulin-related hemolysis: A systematic review of clinical trial and real-world populations.

BACKGROUND: Severe hemolysis rarely occurs in patients receiving intravenous immunoglobulin (IVIG) therapy. A systematic review was performed to assess the incidence of IVIG-related hemolysis and the impact of patient and product risk factors. STUDY DESIGN AND METHODS: A systematic literature search for terms related to "IVIG products", "hemolysis," and "adverse events" was conducted in Embase for articles published between January 1, 2015, and May 31, 2021. Studies with no clinical datasets, no IVIG treatment, or where IVIG was used to treat hemolytic conditions were excluded. Of the 430 articles retrieved, 383 were excluded based on titles/abstracts and 14 were excluded after in-depth review. RESULTS: In total, 33 articles were analyzed and separated into observational studies (n = 16), clinical trials (n = 8), and case reports (n = 9). The incidence proportion for IVIG-related hemolysis ranged from 0% to 19% in observational studies and 0%-21% in clinical trials. A higher incidence of IVIG-related hemolysis was consistently reported in patients with blood groups A and AB. Hemolysis occurred more frequently in patients treated with IVIG for some conditions such as Kawasaki disease; however, this may be confounded by the high dose of IVIG therapy. IVIG-related hemolysis incidence was lower in studies using IVIG products citing manufacturing processes to reduce isoagglutinin levels than products that did not. CONCLUSION: This analysis identified patient and product risk factors including blood group, IVIG dose, and IVIG manufacturing processes associated with elevated IVIG-related hemolysis incidence.

Effects of the manufacturing process on the anti-A isoagglutinin titers in intravenous immunoglobulin products.

BACKGROUND: The first intravenous immunoglobulin G (IVIG) preparations for clinical use were produced from human plasma by Cohn-like fractionation processes. To achieve higher purity and yield, chromatography-based processes were developed. Using two products as examples, we compare the capacity of these two manufacturing processes to reduce the levels of anti-A and anti-B isoagglutinins in IVIG, which are believed to be responsible for rare hemolytic adverse events. STUDY DESIGN AND METHODS: The isoagglutinin levels of Sandoglobulin (lyophilized, sucrose-stabilized IVIG produced by Cohn-like fractionation) and Privigen (10% l-proline-stabilized IVIG produced by a chromatography-based process) were measured by the indirect agglutination test (IAT). The intrinsic isoagglutinin reduction capacity of each fractionation step was assessed in laboratory- and industry-scale experiments using the IAT and a flow cytometry-based immunoglobulin-binding assay, respectively. RESULTS: The median anti-A isoagglutinin titer recorded in 248 Sandoglobulin lots was three titer steps lower than the one measured in 651 Privigen lots (1:2 vs. 1:16). Over the entire process, we measured a five-titer-step isoagglutinin reduction in laboratory-scale Cohn-like fractionation; the largest reduction was observed between Fraction (F)II+III and FII. An overall four-titer-step reduction was recorded in the industry-scale process. In contrast, none of the steps of the chromatography-based manufacturing process caused any decrease in anti-A isoagglutinin content. Similar results were obtained for anti-B isoagglutinin reduction. CONCLUSION: Unlike Cohn-like fractionation, chromatography-based IVIG manufacturing processes do not have an intrinsic capacity for isoagglutinin reduction. The addition of dedicated isoagglutinin reduction steps may help minimize the potential risk of hemolysis in IVIG-treated patients.

Isoagglutinin reduction by a dedicated immunoaffinity chromatography step in the manufacturing process of human immunoglobulin products.

BACKGROUND: The passive transfer of antibodies specific to blood groups A and B (also called isoagglutinins) contained in immunoglobulin (Ig)G products for intravenous administration (IVIG) is believed to be largely responsible for rare but sometimes serious IVIG-related hemolytic events. We present in this work a modification of the manufacturing process of Privigen-a 10% l-proline-stabilized IVIG product-that allows extensive reduction of isoagglutinin concentrations in the final product. STUDY DESIGN AND METHODS: An additional immunoaffinity chromatography (IAC) step was introduced toward the end of the manufacturing process of Privigen. Isoagglutinin titers were measured using the indirect agglutination method and a published flow cytometry-based binding assay. Quality attributes, such as microorganism counts and concentration of endotoxins, IgG, IgA, IgM, aggregates, and so forth were measured using standardized procedures. RESULTS: The introduction of an IAC step in the manufacturing process of Privigen resulted in an 88% to 90% reduction in isoagglutinins between the feed of the chromatography column and the flow-through fraction. All other product quality attributes measured were nearly identical before and after IAC. This process modification resulted in a three-titer-step reduction in isoagglutinin levels in the final IgG product compared to Privigen lots produced by the unmodified process. CONCLUSION: Introducing an isoagglutinin-specific IAC step in the manufacturing process of Privigen is an efficient strategy for reduction of anti-A and anti-B titers. Such reductions might help minimize the risk of hemolytic events in patients receiving IVIG therapy.

Influence of inhaled nitric oxide on plasma nitrate concentrations in patients with adult respiratory distress syndrome and sepsis: results of a pilot study.

STUDY OBJECTIVE: To measure plasma nitrate concentrations after inhalation of nitric oxide for treatment of adult respiratory distress syndrome (ARDS) and sepsis. DESIGN: Prospective pilot study. SETTING: Intensive care unit at a university-affiliated hospital. PATIENTS: Nine consecutive medical intensive care unit patients with ARDS and sepsis. INTERVENTIONS: After diagnosis of ARDS, all patients received a balloon-tipped triple-lumen thermodilution pulmonary artery catheter (Baxter Healthcare Corp, Irvine, CA). Inhaled nitric oxide was initiated starting at a dose of one part per million and titrated according to the maximal achievable increase in arterial oxygenation. Hemodynamic measurements including intrapulmonary shunt fraction and blood as analyses were performed before nitric oxide application, as well as 1 and 24 hours after starting nitric oxide, respectively. Plasma samples for determination of nitrate were taken from the arterial line and from the pulmonary thermodilution catheter and analyzed using high-performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: Eight of 9 patients were nitric oxide responders (intrapulmonary shunt decrease >5%). There was no statistically significant increase in nitrate plasma concentration measured both in peripheral arterial and in mixed venous blood with inhaled nitric oxide up to a concentration of 40 parts per million. CONCLUSION: Inhalation of nitric oxide in patients with ARDS and sepsis does not result in increased plasma nitrate concentrations.

Single-dose pharmacokinetics of ofloxacin during continuous venovenous hemofiltration in critical care patients.

BACKGROUND: Ofloxacin is a quinolone administered to patients with severe infections. Pharmacokinetic data on ofloxacin in critically ill patients on renal replacement therapy are sparse and conflicting. METHODS: Eight patients with anuric acute renal failure were administered 400 mg of ofloxacin intravenously. The pharmacokinetics of ofloxacin was analyzed during continuous venovenous hemofiltration (CVVH) with a high-flux polysulfone membrane. Serum and ultrafiltrate levels of ofloxacin were measured by means of high-performance liquid chromatography. RESULTS: Mean serum ofloxacin concentration peak was 5.5 +/- 0.7 mg/L. Elimination half-life, hemofiltration clearance, and total removal were 2.8 +/- 0.5 hours, 89.9 +/- 4.5 mL/min, and 76.9% +/- 7.1%, respectively. CONCLUSION: Ofloxacin is significantly and rapidly eliminated by CVVH with a high-flux polysulfone membrane.