Complement Inhibition in Severe COVID-19 Acute Respiratory Distress Syndrome

Raghunandan, Sharmila; Josephson, Cassandra D.; Verkerke, Hans; Linam, W. Matthew; Ingram, Treva C; Zerra, Patricia E.; Arthur, Connie M.; Stowell, Sean R.; Briones, Michael; Chonat, Satheesh

doi:10.3389/fped.2020.616731

Cited by 8 publications

(4 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recently published case report demonstrated that C5a was not blocked in a patient who had been treated with the C5 inhibitor eculizumab. 4 Furthermore, a recently published study of eculizumab for treatment of patients with severe COVID‐19 5 showed no difference in C5a concentrations between eculizumab‐treated and eculizumab‐free patients at day 1 and day 7. 6 Another potential advantage of direct inhibition of C5a compared with upstream inhibition, such as C5 or C3 inhibition, is that C5b and C5b‐9 and the membrane attack complex (MAC) formation are left intact.…”

Section: Discussionmentioning

confidence: 99%

“…Especially thrombin, but also other enzymes will be abundant and highly active. A recently published case report demonstrated that C5a was not blocked in a patient who had been treated with the C5 inhibitor eculizumab 4 . Furthermore, a recently published study of eculizumab for treatment of patients with severe COVID‐19 5 showed no difference in C5a concentrations between eculizumab‐treated and eculizumab‐free patients at day 1 and day 7 6 .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The anti‐C5a antibody vilobelimab efficiently inhibits C5a in patients with severe COVID‐19

Vlaar

Lim

Bruin

et al. 2022

Clinical Translational Sci

View full text Add to dashboard Cite

Recently, we reported the phase II portion of the adaptive phase II/III PANAMO trial exploring potential benefit and safety of selectively blocking C5a with the monoclonal antibody vilobelimab (IFX‐1) in patients with severe coronavirus disease 2019 (COVID‐19). The potent anaphylatoxin C5a attracts neutrophils and monocytes to the infection site, causes tissue damage by oxidative radical formation and enzyme releases, and leads to activation of the coagulation system. Results demonstrated that C5a inhibition with vilobelimab was safe and secondary outcomes appeared in favor of vilobelimab. We now report the pharmacokinetic/pharmacodynamic (PK/PD) analysis of the phase II study. Between March 31 and April 24, 2020, 30 patients with severe COVID‐19 pneumonia confirmed by real‐time polymerase chain reaction were randomly assigned 1:1 to receive vilobelimab plus best supportive care or best supportive care only. Samples for measurement of vilobelimab, C3a and C5a blood concentrations were taken. Vilobelimab predose (trough) drug concentrations in plasma ranged from 84,846 to 248,592 ng/ml (571 to 1674 nM) with a geometric mean of 151,702 ng/ml (1022 nM) on day 2 and from 80,060 to 200,746 ng/ml (539 to 1352 nM) with a geometric mean of 139,503 ng/ml (939 nM) on day 8. After the first vilobelimab infusion, C5a concentrations were suppressed in the vilobelimab group (median 39.70 ng/ml 4.8 nM, IQR 33.20–45.55) as compared to the control group (median 158.53 ng/ml 19.1 nM, IQR 60.03–200.89, p = 0.0006). The suppression was maintained on day 8 ( p = 0.001). The current PK/PD analysis shows that vilobelimab efficiently inhibits C5a in patients with severe COVID‐19.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The anti‐C5a antibody vilobelimab efficiently inhibits C5a in patients with severe COVID‐19

Vlaar

Lim

Bruin

et al. 2022

Clinical Translational Sci

View full text Add to dashboard Cite

show abstract

“…It was therefore hypothesized that excessive complement activation contributes to disease progression and severity (126). Indeed, complement inhibition using antibodies directed against C5a (127), C5 (128,129), and C3 (130) are currently being tested.…”

Section: Dysregulation Of the Complement Cascadementioning

confidence: 99%

Immune Dysregulation and the Increased Risk of Complications and Mortality Following Respiratory Tract Infections in Adults With Down Syndrome

et al. 2021

View full text Add to dashboard Cite

The risk of severe outcomes following respiratory tract infections is significantly increased in individuals over 60 years, especially in those with chronic medical conditions, i.e., hypertension, diabetes, cardiovascular disease, dementia, chronic respiratory disease, and cancer. Down Syndrome (DS), the most prevalent intellectual disability, is caused by trisomy-21 in ~1:750 live births worldwide. Over the past few decades, a substantial body of evidence has accumulated, pointing at the occurrence of alterations, impairments, and subsequently dysfunction of the various components of the immune system in individuals with DS. This associates with increased vulnerability to respiratory tract infections in this population, such as the influenza virus, respiratory syncytial virus, SARS-CoV-2 (COVID-19), and bacterial pneumonias. To emphasize this link, here we comprehensively review the immunobiology of DS and its contribution to higher susceptibility to severe illness and mortality from respiratory tract infections.

show abstract

“…The complement system is a key part of the innate immune system which plays an important role in defense against foreign pathogens such as viruses but, in addition to being an important part of the immune defense system, it plays a critical role in promoting the inflammatory process that leads to organ dysfunction [21]. Although several studies have been carried out on the complement system in COVID-19 and its relationship with clinical outcomes [5,6,8,12,25], they did not indicate a clear protective or adverse effect of this system.…”

Section: Introductionmentioning

confidence: 99%

Associations between serum levels of C3, C4, and total classical complement activity in COVID-19 patients at the time of admission and clinical outcome

Razi

Azimian

Arezumand

et al. 2023

Russian Journal of Infection and Immunity

View full text Add to dashboard Cite

In the present study, we investigated the association between complement system status at the time of admission and clinical outcomes in COVID-19 patients. This single-center study was carried out with sixty-one adult patients with COVID-19 who were hospitalized at Imam Hassan Hospital of North Khorasan University of Medical Sciences (Bojnurd, Iran) with less than three days passage since onset of COVID-19 symptoms. Twenty-three healthy volunteers with demographic features similar to the patient group (matched by age and gender) were included in the study as a control group. Patient information including demographic information, demographic data, clinical characteristics, and clinical outcomes were obtained from electronic medical records. Of 61 hospitalized patients with COVID-19, 28 (47.54%) were female, and the average age was 48.78.8 years. The healthy control group included 23 cases (11 (47.8%) female, 12 (52.1%) males, mean age 46.44.4 years). Twenty-one of the 61 patients (34.4%) were admitted to the ICU, and sixteen of them (26.2%) died. Thirty-three (54.10%) patients with COVID-19 were hospitalized for less than 7 days, and 28 (45.90%) of them were hospitalized for 7 days. Our results show that length of hospital stay in the no-ICU group was significantly lower than the ICU admission or death groups (6.490.24 vs. 8.851.59 and 10.531.80, p = 0.0002). The levels of C3, C4, and CH50 were determined through the immunoturbidimetric method and single-radial-haemolysis plates, respectively, on serum samples obtained from patients at the time of admission or those in the control group. Our results indicate that C3, C4 and CH50 levels were markedly lower in COVID-19 patients than in the control group. We also found that complement parameter levels in COVID-19 patients who died or were admitted to ICU were significantly lower than in non-ICU COVID-19 patients. In general, it seems that serum level of C3, C4, and CH50 at admission may predict disease progression or adverse clinical outcome in COVID-19 patients.

show abstract

Complement Inhibition in Severe COVID-19 Acute Respiratory Distress Syndrome

Cited by 8 publications

References 32 publications

The anti‐C5a antibody vilobelimab efficiently inhibits C5a in patients with severe COVID‐19

The anti‐C5a antibody vilobelimab efficiently inhibits C5a in patients with severe COVID‐19

Immune Dysregulation and the Increased Risk of Complications and Mortality Following Respiratory Tract Infections in Adults With Down Syndrome

Associations between serum levels of C3, C4, and total classical complement activity in COVID-19 patients at the time of admission and clinical outcome

Contact Info

Product

Resources

About