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Identifying Safety Thresholds for Immunosuppressive Drugs: Applying Insights from Primary Antibody Deficiencies to Mitigate Adverse Events in Secondary Antibody Deficiencies Using Mathematical Modeling of Preclinical and Early Clinical Data.

ABSTRACT: Immunosuppressive drugs can alleviate debilitating symptoms of autoimmune diseases, but, by the same token, excessive immune suppression can result in an increased risk of infection. Despite the dangers of a compromised immune system, clear definitions of what constitutes excessive suppression remain elusive. Here we review the most common infections associated with primary antibody deficiencies (PADs), such as agammaglobulinemia, common variable immunodeficiency (CVID), and IgA deficiency, as well as infections that are associated with drug-induced or secondary antibody immunodeficiencies (SADs). We identify a number of bacterial, viral, and fungal infections (e.g., Listeria monocytogenes, Staphylococcus sp., Salmonella spp., Escherichia coli, influenza, varicella zoster virus, and herpes simplex virus) associated with both PADs and SADs, and suggest that diagnostic criteria for PADs could be used as a first-line measure to identify potentially unsafe levels of immune suppression in SADs. Specifically, we suggest that, based on PAD diagnostic criteria, IgG levels should remain above 2-3 g/L, IgA levels should not fall below 0.07 g/L, and IgM levels should remain above 0.4 g/L to prevent immunosuppressive drugs from inducing mimicking PAD-like effects. We suggest that these criteria could be used in the early stages of drug development, and that pharmacokinetic and pharmacodynamic modeling could help guide patient selection to potentially improve drug safety. We illustrate the proposed approach using atacicept as an example and conclude with a discussion of the applicability of this approach for other drugs that may induce excessive immune suppression.

SUBMITTER: Kareva I

PROVIDER: S-EPMC8478771 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportancePotentially preventable adverse events remain a formidable cause of patient harm and health care expenditure despite advances in systems-based risk-reduction strategies.ObjectiveTo analyze and describe the incidence of human performance deficiencies (HPDs) during the provision of surgical care to identify opportunities to enhance patient safety.Design, setting, and participantsThis quality improvement study used a new taxonomy to inform the development and implementation of an HPD classifier tool to categorize HPDs into errors associated with cognitive, technical, and team dynamic functions. The HPD classifier tool was then used to concurrently analyze surgical adverse events in 3 adult hospital affiliates-a level I municipal trauma center, a quaternary care university hospital, and a US Veterans Administration hospital-from January 2, 2018, to June 30, 2018. Surgical trainees presented data describing all adverse events associated with surgical services at weekly hospital-based morbidity and mortality conferences. Adverse events and HPDs were classified in discussion with attending faculty and residents. Data were analyzed from July 9, 2018, to December 23, 2018.Main outcomes and measuresThe incidence and primary and secondary causes of HPDs were classified using an HPD classifier tool.ResultsA total of 188 adverse events were recorded, including 182 adverse events (96.8%) among 5365 patients who underwent surgical operations and 6 adverse events (3.2%) among patients undergoing nonoperative treatment. Among these 188 adverse events, 106 (56.4%) were associated with HPDs. Among these 106 HPD adverse events, a total of 192 HPDs (mean [SD], 1.8 [0.9] HPDs per HPD event) were identified. Human performance deficiencies were categorized as execution (98 HPDs [51.0%]), planning or problem solving (55 HPDs [28.6%]), communication (24 HPDs [12.5%]), teamwork (9 HPDs [4.7%]), and rules violation (6 HPDs [3.1%]). Human performance deficiencies most commonly presented as cognitive errors in execution of care or in case planning or problem solving (99 of 192 HPDs [51.6%]). In contrast, technical execution errors without other associated HPDs were observed in 20 of 192 HPDs (10.4%).Conclusions and relevanceHuman performance deficiencies were identified in more than half of adverse events, most commonly associated with cognitive error in the execution of care. These data provide a framework and impetus for new quality improvement initiatives incorporating cognitive training to mitigate human error in surgery.

Dataset Information

Identifying Safety Thresholds for Immunosuppressive Drugs: Applying Insights from Primary Antibody Deficiencies to Mitigate Adverse Events in Secondary Antibody Deficiencies Using Mathematical Modeling of Preclinical and Early Clinical Data.

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