Serum Complement C3 and C4 and COVID-19 Severity and Mortality: A Systematic Review and Meta-Analysis With Meta-Regression

Zinellu, Angelo; Mangoni, Arduino A.

doi:10.3389/fimmu.2021.696085

Cited by 69 publications

(64 citation statements)

References 44 publications

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“…Of notice we see the most pronounced spreading/distribution in the moderate group. The findings agree with a recent study conducting a systematic review and meta-analysis, investigating possible differences in the serum concentrations of the complement components, C4 and C3, in COVID-19 patients with different severity and survival status (33). The conclusion was that both C4 and C3 levels were significantly lower in patients with high disease severity or non-survivor status than patients with low severity or survivor status, indicating that C4 and C3 are more readily consumed in patients with a severe or fatal course of the disease.…”

Section: Discussionsupporting

confidence: 92%

SARS-CoV-2 Antibodies Mediate Complement and Cellular Driven Inflammation

et al. 2021

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The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to constitute a serious public health threat worldwide. Protective antibody-mediated viral neutralization in response to SARS-CoV-2 infection has been firmly characterized. Where the effects of the antibody response are generally considered to be beneficial, an important biological question regarding potential negative outcomes of a SARS-CoV-2 antibody response has yet to be answered. We determined the distribution of IgG subclasses and complement activation levels in plasma from convalescent individuals using in-house developed ELISAs. The IgG response towards SARS-CoV-2 receptor-binding domain (RBD) after natural infection appeared to be mainly driven by IgG1 and IgG3 subclasses, which are the main ligands for C1q mediated classical complement pathway activation. The deposition of the complement components C4b, C3bc, and TCC as a consequence of SARS-CoV-2 specific antibodies were depending primarily on the SARS-CoV-2 RBD and significantly correlated with both IgG levels and disease severity, indicating that individuals with high levels of IgG and/or severe disease, might have a more prominent complement activation during viral infection. Finally, freshly isolated monocytes and a monocyte cell line (THP-1) were used to address the cellular mediated inflammatory response as a consequence of Fc-gamma receptor engagement by SARS-CoV-2 specific antibodies. Monocytic Fc gamma receptor charging resulted in a significant rise in the secretion of the pro-inflammatory cytokine TNF-α. Our results indicate that SARS-CoV-2 antibodies might drive significant inflammatory responses through the classical complement pathway and via cellular immune-complex activation that could have negative consequences during COVID-19 disease. We found that increased classical complement activation was highly associated to COVID-19 disease severity. The combination of antibody-mediated complement activation and subsequent cellular priming could constitute a significant risk of exacerbating COVID-19 severity.

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Section: Discussionsupporting

confidence: 92%

SARS-CoV-2 Antibodies Mediate Complement and Cellular Driven Inflammation

et al. 2021

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“…The levels of complement C4 were decreased from day 0 to day 10 in patients hospitalized for more than two weeks, but not in patients who were discharged earlier [41]. In a recent meta-analysis, a strong correlation between COVID-19 severity and mortality and C3 and C4 contents was found, which indicate reduced complement activation [42]. Furthermore, C3 and C4 may be helpful in identifying patients who are at high risk of negative clinical outcomes [42].…”

Section: Associations Of Biomarkers With Anti-sars-cov-2 Igg Antibodi...mentioning

confidence: 99%

“…In a recent meta-analysis, a strong correlation between COVID-19 severity and mortality and C3 and C4 contents was found, which indicate reduced complement activation [42]. Furthermore, C3 and C4 may be helpful in identifying patients who are at high risk of negative clinical outcomes [42]. However, in a previous analysis, no major variations in complement C3 or C4 levels were observed between severe and less severe COVID-19 study groups [43], whereas another report found increased C3 and C4 in COVID-19 patients [44].…”

Section: Associations Of Biomarkers With Anti-sars-cov-2 Igg Antibodi...mentioning

confidence: 99%

Increased Serum Thromboxane A2 and Prostacyclin but Lower Complement C3 and C4 Levels in COVID-19: Associations with Chest CT Scan Anomalies and Lowered Peripheral Oxygen Saturation

Al‐Hakeim

Al-Hamami

Almulla

et al. 2021

COVID

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COVID-19 patients suffer from hypercoagulation and activated immune-inflammatory pathways. The current study examined the relationship between specific complements and coagulation abnormalities associated with chest CT scan anomalies (CCTAs) and peripheral oxygen saturation (SpO2) in COVID-19 patients. Serum levels of complement C3 and C4, and thromboxane A2 (TxA2) and prostacyclin (PGI2) were measured using an ELISA and albumin, calcium, and magnesium by using the spectrophotometric method in 60 COVID-19 patients and 30 controls. C3 and C4 were significantly decreased (p < 0.001), and TxA2 and PGI2 significantly increased (p < 0.001) in the COVID-19 patients compared with the controls with the highest levels in the CCTA patients’ group. Neural networks showed that a combination of C3, albumin, and TxA2 yielded a predictive accuracy of 100% in detecting COVID-19 patients. SpO2 was significantly decreased in the COVID-19 patients and was inversely associated with TxA2 and PGI2, and positively with C3, C4, albumin, and calcium. Patients with positive IgG results show significantly higher SpO2, TxA2, PGI2, and C4 levels than IgG-negative patients. CCTAs were accompanied by lower SpO2 and albumin and increased PGI2 and TxA2 levels, suggesting that interactions between immune-inflammatory pathways and platelet hyperactivity participate in the pathophysiology of COVID-19 and, consequently, may play a role in an enhanced risk of hypercoagulability and venous thromboembolism. These mechanisms are aggravated by lowered calcium and magnesium levels.

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“… 27 , 28 , 29 , 30 The larger viral load levels in critically ill patients could lead to a relative increase in the probability of transmission of 24% to 58% in household contacts, and of 15% to 39% in non-household contacts. [28] Contrary to low concentrations of serum C3 and C4, which indicate compliment activation [29] , the viral load of SARS-CoV-2 in nasopharyngeal swab appears insignificant for predicting COVID-19 severity and prognosis[ 8 , 24 , 30 ], and may not be related to surface contamination. Last but not least, our study was performed before the pandemic of the Omicron (B1.1.529) variant.…”

Section: Discussionmentioning

confidence: 99%

Inanimate surface contamination of SARS-CoV-2 during midfacial fracture repair in asymptomatic COVID-19 patients

Pitak‐Arnnop¹,

Sirintawat²,

Tangmanee³

et al. 2022

Journal of Stomatology, Oral and Maxillofacial Surgery

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Purposes To evaluate inanimate surface contamination of SARS-CoV-2 during midfacial fracture repair (MFR) and to identify relevant aggregating factors. Methods Using a prospective non-randomised comparative study design, we enrolled a cohort of asymptomatic COVID-19 patients undergoing MFR. The predictor variables were osteofixation system (conventional titanium plates [CTiP] vs. ultrasound-assisted resorbable plates [USaRP]). The main outcomes were the presence of SARS-CoV-2 on four different surfaces. Other study variables were categorised into demographic, anatomic, and operative. Descriptive, bi- and multivariate statistics were computed. Results The sample consisted of 11 patients (27.3% females. 63.6% right side, 72.7% displaced fractures) with a mean age of 52.7 ± 20.1 years (range, 19-85). Viral spread was, on average, 1.9 ± 0.4 m. from the operative field, including most oral and orbital retractors’ tips (81.8% and 72.7%) and no virus was found at 3 m from the operative field, but no significant difference was found between 2 osteofixation types. On binary adjustments, significantly broader contamination was linked to centrolateral MFR ( P = 0.034; 95% confidence interval [CI], 0.05 to 1.02), and displaced MFR > 45 min ( P = 0.022; 95% CI, 0.1 to 1.03). Conclusions USaRP, albeit presumably heavily aerosol-producing, cause similar SARS-CoV-2 distribution to CTiP. Non-surgical operating room (OR) staff should stay ≥ 3 m from the operative field, if the patient is SARS-CoV-2-positive. Enoral and orbital instruments are a potential virus source, especially during displaced MFR > 45 min and/or centrolateral MFR, emphasising an importance of appropriate patient screening and OR organisation.

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Serum Complement C3 and C4 and COVID-19 Severity and Mortality: A Systematic Review and Meta-Analysis With Meta-Regression

Cited by 69 publications

References 44 publications

SARS-CoV-2 Antibodies Mediate Complement and Cellular Driven Inflammation

SARS-CoV-2 Antibodies Mediate Complement and Cellular Driven Inflammation

Increased Serum Thromboxane A2 and Prostacyclin but Lower Complement C3 and C4 Levels in COVID-19: Associations with Chest CT Scan Anomalies and Lowered Peripheral Oxygen Saturation

Inanimate surface contamination of SARS-CoV-2 during midfacial fracture repair in asymptomatic COVID-19 patients

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