ArticleClinical immunology (Orlando, Fla.)2020
Complement C3 vs C5 inhibition in severe COVID-19: Early clinical findings reveal differential biological efficacy.
Article in Clinical immunology (Orlando, Fla.), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 160 papers, 4 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
160 citing papers in PubMed, 4 syntheses or guidelines pooled it, 265 citations in OpenAlex.
- Identifying and profiling structural similarities between Spike of SARS-CoV-2 and other viral or host proteins with Machaon.Communications biology · 2023Pooled it
- A systematic review on neutrophil extracellular traps and its prognostication role in COVID-19 patients.Immunologic research · 2022Pooled it
- Pitfalls in complement analysis: A systematic literature review of assessing complement activation.Frontiers in immunology · 2022Pooled it
- Shared inflammatory pathways and therapeutic strategies in COVID-19 and cancer immunotherapy.Journal for immunotherapy of cancer · 2021Pooled it
- Immunomodulatory role of Nanocurcumin in COVID-19 patients with dropped natural killer cells frequency and function.European journal of pharmacology · 2022Trial
- Efficacy and safety of the investigational complement C5 inhibitor zilucoplan in patients hospitalized with COVID-19: an open-label randomized controlled trial.Respiratory research · 2022Trial
- Complement blockade with eculizumab for treatment of severe Coronavirus Disease 2019 in pregnancy: A case series.American journal of reproductive immunology (New York, N.Y. : 1989) · 2022Trial
- A randomized diet-induced weight-loss intervention reduces plasma complement C3: Possible implication for endothelial dysfunction.Obesity (Silver Spring, Md.) · 2022Trial
- Phase IIa clinical trial of complement C3 inhibitor AMY-101 in adults with periodontal inflammation.The Journal of clinical investigation · 2021Trial
- Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis.The Journal of clinical investigation · 2020Trial
- The Complement System in the Setting of Critical Illness-A Narrative Review.Biomolecules · 2026Review
- Disease-Causing Mechanisms and Therapeutic Targets in Infectious Diseases: Implications for Clinical Management and Public Health.Biomedicines · 2026Review
- Clinical and Immunological Recovery Trajectories in Severe COVID-19 Survivors: A 12-Month Prospective Follow-Up Study.Viruses · 2025Article
- Impact of complement system proteins on the clinical progression of hospitalized patients with COVID-19.BMC infectious diseases · 2025Article
- Enigmatic Roles of Complement Anaphylatoxin Signaling in Health and Disease.Immune network · 2025Review
- Complement Activation is More Pronounced in the Kidneys of Critically Ill Patients With COVID-19 Than in Those With Bacterial Sepsis.Kidney international reports · 2025Article
- Clinical Value of Complement C3a, C5a, and sC5b-9 in Evaluating the Severity of Patients with Severe Fever with Thrombocytopenia Syndrome.Journal of inflammation research · 2025Article
- Scoping review about pathogenesis, risk factors, and treatment of venous and arterial thrombosis in coronavirus infection.Frontiers in cardiovascular medicine · 2025Review
- Viral infections and related fatal adverse events associated with complement inhibitors for PNH: a real-world pharmacovigilance analysis in FAERS.Frontiers in pharmacology · 2025Article
- Immunity and Coagulation in COVID-19.International journal of molecular sciences · 2024Review
100 more citing papers are in PubMed but not listed here.
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Authors and funding
23 authors at 13 institutions in 6 countries.
Funding
Abstract
Growing clinical evidence has implicated complement as a pivotal driver of COVID-19 immunopathology. Deregulated complement activation may fuel cytokine-driven hyper-inflammation, thrombotic microangiopathy and NET-driven immunothrombosis, thereby leading to multi-organ failure. Complement therapeutics have gained traction as candidate drugs for countering the detrimental consequences of SARS-CoV-2 infection. Whether blockade of terminal complement effectors (C5, C5a, or C5aR1) may elicit similar outcomes to upstream intervention at the level of C3 remains debated. Here we compare the efficacy of the C5-targeting monoclonal antibody eculizumab with that of the compstatin-based C3-targeted drug candidate AMY-101 in small independent cohorts of severe COVID-19 patients. Our exploratory study indicates that therapeutic complement inhibition abrogates COVID-19 hyper-inflammation. Both C3 and C5 inhibitors elicit a robust anti-inflammatory response, reflected by a steep decline in C-reactive protein and IL-6 levels, marked lung function improvement, and resolution of SARS-CoV-2-associated acute respiratory distress syndrome (ARDS). C3 inhibition afforded broader therapeutic control in COVID-19 patients by attenuating both C3a and sC5b-9 generation and preventing FB consumption. This broader inhibitory profile was associated with a more robust decline of neutrophil counts, attenuated neutrophil extracellular trap (NET) release, faster serum LDH decline, and more prominent lymphocyte recovery. These early clinical results offer important insights into the differential mechanistic basis and underlying biology of C3 and C5 inhibition in COVID-19 and point to a broader pathogenic involvement of C3-mediated pathways in thromboinflammation. They also support the evaluation of these complement-targeting agents as COVID-19 therapeutics in large prospective trials.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.