Complement activation in patients with COVID-19: A novel therapeutic target

Cugno, Massimo; Meroni, Pier Luigi; Gualtierotti, Roberta; Griffini, Samantha; Grovetti, Elena; Torri, A; Panigada, Mauro; Aliberti, Stefano; Blasi, Francesco; Tedesco, Francesco; Peyvandi, Flora

doi:10.1016/j.jaci.2020.05.006

Cited by 228 publications

(271 citation statements)

References 9 publications

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“…21 In particular, complement may be involved in coronavirus pathogenesis, as inferred from the finding that C3 knockout mice infected with SARS-CoV have less lung disease than wild-type mice. 22 Preliminary data provide evidence for activation of complement (sC5b-9 and C5a) in patients with COVID-19, with significantly higher plasma levels in the patients with severe disease than in those with moderate disease. Hence, complement activation has been suggested as a novel therapeutic target in COVID-19.…”

Section: F I G U R Ementioning

confidence: 82%

Rationale for the use of N ‐acetylcysteine in both prevention and adjuvant therapy of COVID‐19

Balansky²,

2020

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COVID‐19 may cause pneumonia, acute respiratory distress syndrome, cardiovascular alterations, and multiple organ failure, which have been ascribed to a cytokine storm, a systemic inflammatory response, and an attack by the immune system. Moreover, an oxidative stress imbalance has been demonstrated to occur in COVID‐19 patients. N‐ Acetyl‐L‐cysteine (NAC) is a precursor of reduced glutathione (GSH). Due to its tolerability, this pleiotropic drug has been proposed not only as a mucolytic agent, but also as a preventive/therapeutic agent in a variety of disorders involving GSH depletion and oxidative stress. At very high doses, NAC is also used as an antidote against paracetamol intoxication. Thiols block the angiotensin‐converting enzyme 2 thereby hampering penetration of SARS‐CoV‐2 into cells. Based on a broad range of antioxidant and anti‐inflammatory mechanisms, which are herein reviewed, the oral administration of NAC is likely to attenuate the risk of developing COVID‐19, as it was previously demonstrated for influenza and influenza‐like illnesses. Moreover, high‐dose intravenous NAC may be expected to play an adjuvant role in the treatment of severe COVID‐19 cases and in the control of its lethal complications, also including pulmonary and cardiovascular adverse events.

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Section: F I G U R Ementioning

confidence: 82%

Rationale for the use of N ‐acetylcysteine in both prevention and adjuvant therapy of COVID‐19

Balansky²,

2020

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“…A total of 777 records were collected by the databases and manual searching. After the exclusion of the duplicates, review articles, case reports, pre‐printed versions without peer‐review, and irrelevant studies by title or abstract screening, 187 studies remained for full‐text review; 52 studies 6,17‐67 were finally included into the meta‐analysis, and 18 studies were included in the qualitative synthesis (Figure 1). A total of 52 records involving 10 614 COVID‐19 patients confirmed between December 25, 2019, and June 1, 2020, were included.…”

Section: Resultsmentioning

confidence: 99%

Ferritin in the coronavirus disease 2019 (COVID‐19): A systematic review and meta‐analysis

Cheng

et al. 2020

Clinical Laboratory Analysis

314

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Objective The coronavirus disease 2019 (COVID‐19) has rapidly developed into a pandemic. Increased levels of ferritin due to cytokine storm and secondary hemophagocytic lymphohistiocytosis were found in severe COVID‐19 patients. Therefore, the aim of this study was to determine the role of ferritin in COVID‐19. Methods Studies investigating ferritin in COVID‐19 were collected from PubMed, EMBASE, CNKI, SinoMed, and WANFANG. A meta‐analysis was performed to compare the ferritin level between different patient groups: non‐survivors versus survivors; more severe versus less severe; with comorbidity versus without comorbidity; ICU versus non‐ICU; with mechanical ventilation versus without mechanical ventilation. Results A total of 52 records involving 10 614 COVID‐19‐confirmed patients between December 25, 2019, and June 1, 2020, were included in this meta‐analysis, and 18 studies were included in the qualitative synthesis. The ferritin level was significantly increased in severe patients compared with the level in non‐severe patients [WMD 397.77 (95% CI 306.51‐489.02), P < .001]. Non‐survivors had a significantly higher ferritin level compared with the one in survivors [WMD 677.17 (95% CI 391.01‐963.33), P < .001]. Patients with one or more comorbidities including diabetes, thrombotic complication, and cancer had significantly higher levels of ferritin than those without (P < .01). Severe acute liver injury was significantly associated with high levels of ferritin, and its level was associated with intensive supportive care, including ICU transfer and mechanical ventilation. Conclusions Ferritin was associated with poor prognosis and could predict the worsening of COVID‐19 patients.

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“…Our study shows evidence of complement activation in patients with severe COVID-19. Other studies have also reported elevated C5a levels in patients with severe and critical disease [ 3 , 4 ] but, to our knowledge, this is the first study to utilize multiple serial samples to track the progression of complement activation throughout the disease course. In addition, by investigating a cohort of maintenance HD patients we were able to obtain samples from a group of patients with mild disease who, if they had not been attending for HD sessions, would likely not have had contact with healthcare services.…”

Section: Discussionmentioning

confidence: 96%

“…Complement is a major component of the innate immune response and elevated levels of plasma C5a, indicating complement C5 activation, have been identified in patients with severe COVID-19 [ 3 , 4 ]. Vasculitis-like lesions in the lungs with fibrin thrombi of small vessels and infiltrates of neutrophils and monocytes have been identified in post-mortem lung tissue from patients with severe COVID-19 [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Temporal changes in complement activation in haemodialysis patients with COVID-19 as a predictor of disease progression

Prendecki

Clarke

Medjeral-Thomas

et al. 2020

Clinical Kidney Journal

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Background Complement activation may play a pathogenic role in patients with severe coronavirus disease 2019 (COVID-19) by contributing to tissue inflammation and microvascular thrombosis. Methods Serial samples were collected from patients receiving maintenance haemodialysis (HD). Thirty-nine patients had confirmed COVID-19 and 10 patients had no evidence of COVID-19. Plasma C5a and C3a levels were measured using enzyme-linked immunosorbent assay. Results We identified elevated levels of plasma C3a and C5a in HD patients with severe COVID-19 compared with controls. Serial sampling identified that C5a levels were elevated prior to clinical deterioration in patients who developed severe disease. C3a more closely mirrored both clinical and biochemical disease severity. Conclusions Our findings suggest that activation of complement plays a role in the pathogenesis of COVID-19, leading to endothelial injury and lung damage. C5a may be an earlier biomarker of disease severity than conventional parameters such as C-reactive protein and this warrants further investigation in dedicated biomarker studies. Our data support the testing of complement inhibition as a therapeutic strategy for patients with severe COVID-19.

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Complement activation in patients with COVID-19: A novel therapeutic target

Cited by 228 publications

References 9 publications

Rationale for the use of N ‐acetylcysteine in both prevention and adjuvant therapy of COVID‐19

Rationale for the use of N ‐acetylcysteine in both prevention and adjuvant therapy of COVID‐19

Ferritin in the coronavirus disease 2019 (COVID‐19): A systematic review and meta‐analysis

Temporal changes in complement activation in haemodialysis patients with COVID-19 as a predictor of disease progression

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