Complement Inhibitors and the Risk of (Breakthrough) Infections—Critical Analysis and Preventive Strategies

A wide variety of nanomaterials are currently being developed for use in the detection and treatment of human diseases. However, there is no systematic way to measure and predict the action of such materials in biological contexts. Lipid-encapsulated nanoparticles (NPs) are a class of nanomaterials that includes the liposomes, the most widely used and clinically proven type of NPs. Liposomes can, however, activate the complement system, an important branch of innate immunity, resulting in undesirable consequences. Here, we describe the complement response to lipid-encapsulated NPs that are functionalized on the surface with various lipid-anchored gadolinium chelates. We developed a quantitative approach to examine the interaction of NPs with the complement system using in vitro assays and correlating these results with those obtained in an in vivo mouse model. Our results indicate that surface functionalization of NPs with certain chemical structures elicits swift complement activation that is initiated by a natural IgM antibody and propagated via the classical pathway. The intensity of the response is dependent on the chemical structures of the lipid-anchored chelates and not zeta potential effects alone. Moreover, the extent of complement activation may be tempered by complement inhibiting regulatory proteins that bind to the surface of NPs. These findings represent a step forward in the understanding of the interactions between nanomaterials and the host innate immune response and provide the basis for a systematic structure-activity relationship study to establish guidelines that are critical to the future development of biocompatible nanotherapeutics.

Is complement a target for therapy in renal disease?

Microbial complement evasion and vaccine development.

By virtue of its amplifying property, the alternative complement pathway has been implicated in a number of inflammatory diseases and constitutes an attractive therapeutic target. An anti-factor D Fab fragment (AFD) was generated to inhibit the alternative complement pathway in advanced dry age-related macular degeneration. AFD potently prevented factor D (FD)-mediated proteolytic activation of its macromolecular substrate C3bB, but not proteolysis of a small synthetic substrate, indicating that AFD did not block access of the substrate to the catalytic site. The crystal structures of AFD in complex with human and cynomolgus FD (at 2.4 and 2.3 Å, respectively) revealed the molecular details of the inhibitory mechanism. The structures show that the AFD-binding site includes surface loops of FD that form part of the FD exosite. Thus, AFD inhibits FD proteolytic function by interfering with macromolecular substrate access rather than by inhibiting FD catalysis, providing the molecular basis of AFD-mediated inhibition of a rate-limiting step in the alternative complement pathway.

The CDC estimates 23% of healthcare-associated infections to be surgical site infections, with alarming prevalence of antibiotic-resistant organisms. While there is consensus regarding preoperative prophylaxis, orthopaedic surgeons' use of prophylactic postoperative oral antibiotics is less defined. We investigated surgeons' use of prophylactic postoperative oral antibiotics after elective outpatient foot or ankle procedures, identifying (1) frequency of use, (2) regimen preferences, (3) personal indications, and (4) associated experience and demographics. Using a cross-sectional survey design, a questionnaire was emailed to all active and candidate members of the American Orthopaedic Foot and Ankle Society. Supplementary questions captured demographic information. We invited 1136 members to participate; 22 addresses produced delivery failure messages, leaving 1114 members as potential participants. After nonresponses and exclusions, 312 (28%) responses were analyzed. Statistical analysis used Pearson's chi-square test, Fisher's exact test, and multivariate regression. The majority (75%) of respondents reported use of prophylactic postoperative oral antibiotics. Most users (69%) prescribed to fewer than 25% of patients, although 16% prescribed for all elective cases. The most frequent regimen was cephalexin 500 mg four times a day (63%) and the most common duration was 5 to 7 days (50%). Surgeons' most common indications were previous infection (71%), medical comorbidities (65%), and previous wound-healing difficulties (56%). Those who do and do not prescribe prophylactic postoperative oral antibiotics showed no difference in surgical site infection rate or any demographic category. Surgeons' reported use of prophylactic postoperative oral antibiotics after elective foot or ankle surgery was common, without demographic association. Commonalities were identified in antibiotic regimen and personal indications for this practice. Comparative clinical studies are warranted to elucidate the efficacy of prophylactic postoperative oral antibiotics and establish evidence-based guidelines for their use.

Will Complement Inhibition Be the New Target in Treating COVID-19-Related Systemic Thrombosis?

A Novel C5 Complement Inhibitor Protects Against Sepsis-Induced Activation of Complement, Coagulation and Inflammation and Provides Survival Benefit in E. coli Sepsis

C-reactive protein in myocardial infarction binds to circulating microparticles but is not associated with complement activation

Complement in Glomerular Disease

POS-042 C3d-Directed Factor H Targeting Delivers Potent and Durable Complement Inhibition and Disease-Modifying Efficacy In Kidney and Skin Without Inhibiting Systemic Complement

Prognostic Significance of Complement System Activation After Allogeneic Hematopoietic Stem Cell Transplantation.

High-dose Mycophenolate Use at Vaccination Is Independently Associated With Breakthrough COVID-19 Among Lung Transplant Patients.

Prolonged prophylactic antibiotics with neurosurgical drains and devices: Are we using them? Do we need them?

Complement in Lupus Nephritis: The Good, the Bad, and the Unknown

To provide a comparative meta‐analysis and systematic review of the risk and clinical outcomes of coronavirus 2019 (COVID‐19) infection between fully vaccinated and unvaccinated groups. Eighteen studies of COVID‐19 infections in fully vaccinated (“breakthrough infections”) and unvaccinated individuals were reviewed from Medline/PubMed, Scopus, Embase, and Web of Science databases. The meta‐analysis examined the summary effects and between‐study heterogeneity regarding differences in the risk of infection, hospitalization, treatments, and mortality between vaccinated and unvaccinated individuals. he overall risk of infection was lower for the fully vaccinated compared to that of the unvaccinated (relative risk [RR] 0.20, 95% confidence interval [CI]: 0.19−0.21), especially for variants other than Delta (Delta: RR 0.29, 95% CI: 0.13−0.65; other variants: RR 0.06, 95% CI: 0.04−0.08). The risk of asymptomatic infection was not statistically significantly different between fully vaccinated and unvaccinated (RR 0.56, 95% CI: 0.27−1.19). There were neither statistically significant differences in risk of hospitalization (RR 1.06, 95% CI: 0.38−2.93), invasive mechanical ventilation (RR 1.65, 95% CI: 0.90−3.06), or mortality (RR 1.19, 95% CI: 0.79−1.78). Conversely, the risk of supplemental oxygen during hospitalization was significantly higher for the unvaccinated (RR 1.40, 95% CI: 1.08−1.82). Unvaccinated people were more vulnerable to COVID‐19 infection than fully vaccinated for all variants. Once infected, there were no statistically significant differences in the risk of hospitalization, invasive mechanical ventilation, or mortality. Still, unvaccinated showed an increased need for oxygen supplementation. Further prospective analysis, including patients’ risk factors, COVID‐19 variants, and the utilized treatment strategies, would be warranted.