Complement Inhibition and COVID-19: The Story so Far

References

• John Hopkins University. Coronavirus resources center. Available from: https://coronavirus.jhu.edu/map.html. Accessed May 15, 2021.
   Google Scholar
• Osuchowski MF, Winkler MS, Skirecki T, et al. The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity. Lancet Respir Med. 2021;S2213–2600(21):218–226. doi:10.1016/S2213-2600(21)00218-6
   Web of Science ®Google Scholar
• Onodi F, Bonnet-Madin L, Meertens L, et al. SARS-CoV-2 induces human plasmacytoid predendritic cell diversification via UNC93B and IRAK4. J Exp Med. 2021;218(4):e20201387. doi:10.1084/jem.20201387
   PubMed Web of Science ®Google Scholar
• Lee JS, Park S, Jeong HW, et al. Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19. Sci Immunol. 2020;5(49):eabd1554. doi:10.1126/sciimmunol.abd1554
   PubMed Web of Science ®Google Scholar
• Dorgham K, Quentric P, Gökkaya M, et al. Distinct cytokine profiles associated with COVID-19 severity and mortality. J Allergy Clin Immunol. 2021;S0091–S6749(21):651–6555. doi:10.1016/j.jaci.2021.03.047
   Web of Science ®Google Scholar
• Laing AG, Lorenc A, Del Molino Del Barrio I, et al. A dynamic COVID-19 immune signature includes associations with poor prognosis. Nat Med. 2020;26:623–1635. doi:10.1038/s41591-020-01186-5
   Web of Science ®Google Scholar
• Bordet J. Sur le mode d’action des sérums cytolytiques et sur l’unité de l’alexine dans un même sérum. Ann Inst Pasteur. 1901;15:303–318.
   Google Scholar
• Cavaillon JM, Sansonetti P, Goldman M. 100th anniversary of Jules bordet’s Nobel prize: tribute to a founding father of immunology. Front Immunol. 2019;10:2114. doi:10.3389/fimmu.2019.02114
   Web of Science ®Google Scholar
• Bardhan M, Kaushik R. Physiology, Complement Cascade. StatPearls, Treasure Island (FL): StatPearls Publishing; 2021. PMID: 31855355.
   Google Scholar
• Mollnes TE, Huber-Lang M. Complement in sepsis-when science meets clinics. FEBS Lett. 2020;594(16):2621–2632. doi:10.1002/1873-3468.13881
   PubMed Web of Science ®Google Scholar
• Ramlall V, Thangaraj PM, Meydan C, et al. Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection. Nat Med. 2020;26(10):1609–1615. doi:10.1038/s41591-020-1021-2
   PubMed Web of Science ®Google Scholar
• Ehrlich P, Marshall HT. Ueber die complementophilen Gruppen der Amboceptoren. Berliner KlinWochenschr. 1902;39:585–587.
   Google Scholar
• Kemper C, Köhl J. Novel roles for complement receptors in T cell regulation and beyond. Mol Immunol. 2013;56(3):181–190. doi:10.1016/j.molimm.2013.05.223
   Web of Science ®Google Scholar
• Hawlisch H, Belkaid Y, Baelder R, Hildeman D, Gerard C, Köhl J. C5a negatively regulates toll-like receptor 4-induced immune responses. Immunity. 2005;22:415–426. doi:10.1016/j.immuni.2005.02.006
   PubMed Web of Science ®Google Scholar
• Ma N, Xing C, Xiao H, et al. C5a regulates IL-12+ DC migration to induce pathogenic Th1 and Th17 cells in sepsis. PLoS One. 2013;8(7):e69779. doi:10.1371/journal.pone.0069779
   Web of Science ®Google Scholar
• Fusakio ME, Mohammed JP, Laumonnier Y, Hoebe K, Köhl J, Mattner J. C5a regulates NKT and NK cell functions in sepsis. J Immunol. 2011;187(11):5805–5812. doi:10.4049/jimmunol.1100338
   PubMed Web of Science ®Google Scholar
• Riedemann NC, Guo RF, Bernacki KD, et al. Regulation by C5a of neutrophil activation during sepsis. Immunity. 2003;19(2):193–202. doi:10.1016/s1074-7613(03)00206-1
   PubMed Web of Science ®Google Scholar
• Strieter RM, Kasahara K, Allen RM, et al. Cytokine-induced neutrophil-derived interleukin-8. Am J Pathol. 1992;141(2):397–407.
   Web of Science ®Google Scholar
• Riedemann NC, Guo RF, Hollmann TJ, et al. Regulatory role of C5a in LPS-induced IL-6 production by neutrophils during sepsis. FASEB J. 2004;18(2):370–372. doi:10.1096/fj.03-0708fje
   PubMed Web of Science ®Google Scholar
• Yu M, Blomstrand E, Chibalin AV, Krook A, Zierath JR. Marathon running increases ERK1/2 and p38 MAP kinase signalling to downstream targets in human skeletal muscle. J Physiol. 2001;536(Pt1):273–282. doi:10.1111/j.1469-7793.2001.00273.x
   Web of Science ®Google Scholar
• Bosmann M, Patel VR, Russkamp NF, et al. MyD88-dependent production of IL-17F is modulated by the anaphylatoxin C5a via the Akt signaling pathway. FASEB J. 2011;25(12):4222–4232. doi:10.1096/fj.11-191205
   Web of Science ®Google Scholar
• Bosmann M, Sarma JV, Atefi G, Zetoune FS, Ward PA. Evidence for anti-inflammatory effects of C5a on the innate IL-17A/IL-23 axis. FASEB J. 2012;26(4):1640–1651. doi:10.1096/fj.11-199216
   Web of Science ®Google Scholar
• Ward PA. Sepsis, apoptosis and complement. Biochem Pharmacol. 2008;76(11):1383–1388. doi:10.1016/j.bcp.2008.09.017
   Web of Science ®Google Scholar
• Perianayagam MC, Balakrishnan VS, King AJ, Pereira BJ, Jaber BL. C5a delays apoptosis of human neutrophils by a phosphatidylinositol 3-kinase-signaling pathway. Kidney Int. 2002;61(2):456–463. doi:10.1046/j.1523-1755.2002.00139.x
   Web of Science ®Google Scholar
• Guo RF, Sun L, Gao H, et al. In vivo regulation of neutrophil apoptosis by C5a during sepsis. J Leukoc Biol. 2006;80(6):1575–1583. doi:10.1189/jlb.0106065
   Web of Science ®Google Scholar
• Lalli PN, Strainic MG, Yang M, Lin F, Medof ME, Heeger PS. Locally produced C5a binds to T cell-expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis. Blood. 2008;112(5):1759–1766. doi:10.1182/blood-2008-04-151068
   Web of Science ®Google Scholar
• Conway Morris A, Kefala K, Wilkinson TS, et al. C5a mediates peripheral blood neutrophil dysfunction in critically ill patients. Am J Respir Crit Care Med. 2009;180(1):19–28. doi:10.1164/rccm.200812-1928OC
   PubMed Web of Science ®Google Scholar
• Foley JH, Conway EM. Cross talk pathways between coagulation and inflammation. Circ Res. 2016;118(9):1392–1408. doi:10.1161/CIRCRESAHA.116.306853
   PubMed Web of Science ®Google Scholar
• Brekke OL, Waage C, Christiansen D, et al. The effects of selective complement and CD14 inhibition on the E. coli-induced tissue factor mRNA upregulation, monocyte tissue factor expression, and tissue factor functional activity in human whole blood. Adv Exp Med Biol. 2013;735:123–136. doi:10.1007/978-1-4614-4118-2_8
   Web of Science ®Google Scholar
• Landsem A, Fure H, Christiansen D, et al. The key roles of complement and tissue factor in Escherichia coli-induced coagulation in human whole blood. Clin Exp Immunol. 2015;182(1):81–89. doi:10.1111/cei.12663
   PubMed Web of Science ®Google Scholar
• Kalbitz M, Fattahi F, Herron TJ, et al. Complement destabilizes cardiomyocyte function in vivo after polymicrobial sepsis and in vitro. J Immunol. 2016;197(6):2353–2361. doi:10.4049/jimmunol.1600091
   Web of Science ®Google Scholar
• Annane D. Sepsis-associated delirium: the pro and con of C5a blockade. Crit Care. 2009;13(2):135. doi:10.1186/cc7754
   Web of Science ®Google Scholar
• Hammerschmidt DE, Weaver LJ, Hudson LD, Craddock PR, Jacob HS. Association of complement activation and elevated plasma-C5a with adult respiratory distress syndrome. Pathophysiological relevance and possible prognostic value. Lancet. 1980;1(8175):947–949. doi:10.1016/s0140-6736(80)91403-8
   PubMed Web of Science ®Google Scholar
• Rota PA, Oberste MS, Monroe SS, et al. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science. 2003;300(5624):1394–1399. doi:10.1126/science.1085952
   PubMed Web of Science ®Google Scholar
• Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med. 2012;367(19):1814–1820. doi:10.1056/NEJMoa1211721
   PubMed Web of Science ®Google Scholar
• Wang R, Xiao H, Guo R, Li Y, Shen B. The role of C5a in acute lung injury induced by highly pathogenic viral infections. Emerg Microbes Infect. 2015;4(5):e28. doi:10.1038/emi.2015.28
   PubMed Web of Science ®Google Scholar
• Gralinski LE, Sheahan TP, Morrison TE, et al. Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis. mBio. 2018;9(5):e01753–e01818. doi:10.1128/mBio.01753-18
   PubMed Web of Science ®Google Scholar
• Jiang Y, Zhao G, Song N, et al. Blockade of the C5a-C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with MERS-CoV. Emerg Microbes Infect. 2018;7(1):77. doi:10.1038/s41426-018-0063-8
   PubMed Web of Science ®Google Scholar
• Ng WF, To KF, Lam WW, Ng TK, Lee KC. The comparative pathology of severe acute respiratory syndrome and avian influenza A subtype H5N1--a review. Hum Pathol. 2006;37(4):381–390. doi:10.1016/j.humpath.2006.01.015
   PubMed Web of Science ®Google Scholar
• Sun S, Zhao G, Liu C, et al. Inhibition of complement activation alleviates acute lung injury induced by highly pathogenic avian influenza H5N1 virus infection. Am J Respir Cell Mol Biol. 2013;49(2):221–230. doi:10.1165/rcmb.2012-0428OC
   PubMed Web of Science ®Google Scholar
• Gao T, Hu M, Zhang X, et al. Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation. medRxiv. 2020. doi:10.1101/2020.03.29.20041962
   Google Scholar
• Pang RT, Poon TC, Chan KC, et al. Serum proteomic fingerprints of adult patients with severe acute respiratory syndrome. Clin Chem. 2006;52(3):421–429. doi:10.1373/clinchem.2005.061689
   Web of Science ®Google Scholar
• Ohta R, Torii Y, Imai M, Kimura H, Okada N, Ito Y. Serum concentrations of complement anaphylatoxins and proinflammatory mediators in patients with 2009 H1N1 influenza. Microbiol Immunol. 2011;55(3):191–198. doi:10.1111/j.1348-0421.2011.00309.x
   Web of Science ®Google Scholar
• Ip WK, Chan KH, Law HK, et al. Mannose-binding lectin in severe acute respiratory syndrome coronavirus infection. J Infect Dis. 2005;191(10):1697–1704. doi:10.1086/429631
   PubMed Web of Science ®Google Scholar
• Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19. J Infect. 2020;80(6):607–613. doi:10.1016/j.jinf.2020.03.037
   PubMed Web of Science ®Google Scholar
• Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. 2020;220:1–13. doi:10.1016/j.trsl.2020.04.007
   PubMed Web of Science ®Google Scholar
• Holter JC, Pischke SE, de Boer E, et al. Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients. Proc Natl Acad Sci U S A. 2020;117(40):25018–25025. doi:10.1073/pnas.2010540117
   PubMed Web of Science ®Google Scholar
• Peffault de Latour R, Bergeron A, Lengline E, et al. Complement C5 inhibition in patients with COVID-19 - a promising target? Haematologica. 2020;105(12):2847–2850. doi:10.3324/haematol.2020.260117
   PubMed Web of Science ®Google Scholar
• Annane D, Heming N, Grimaldi-Bensouda L, et al. Eculizumab as an emergency treatment for adult patients with severe COVID-19 in the intensive care unit: a proof-of-concept study. EClinicalMedicine. 2020;28:100590. doi:10.1016/j.eclinm.2020.100590
   PubMedGoogle Scholar
• Annane D, Grimaldi-Bensouda L, Fremeaux-Bacchic V. Complement inhibition in severe COVID-19 - blocking C5a seems to be key: author’s reply. EClinicalMedicine. 2021;35:100866. doi:10.1016/j.eclinm.2021.100866
   Google Scholar
• Carvelli J, Demaria O, Vély F, et al. Association of COVID-19 inflammation with activation of the C5a-C5aR1 axis. Nature. 2020;588(7836):146–150. doi:10.1038/s41586-020-2600-6
   PubMed Web of Science ®Google Scholar
• Risitano AM, Mastellos DC, Huber-Lang M, et al. Complement as a target in COVID-19? [published correction appears. Nat Rev Immunol. 2020;20(6):343–344. doi:10.1038/s41577-020-0320-7
   PubMed Web of Science ®Google Scholar
• Garred P, Tenner AJ, Mollnes TE. Therapeutic targeting of the complement system: from rare diseases to pandemics. Pharmacol Rev. 2021;73(2):792–827. doi:10.1124/pharmrev.120.000072
   PubMed Web of Science ®Google Scholar
• Silasi-Mansat R, Zhu H, Popescu NI, et al. Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis. Blood. 2010;116(6):1002–1010. doi:10.1182/blood-2010-02-269746
   PubMed Web of Science ®Google Scholar
• Silasi-Mansat R, Zhu H, Georgescu C, et al. Complement inhibition decreases early fibrogenic events in the lung of septic baboons. J Cell Mol Med. 2015;19(11):2549–2563. doi:10.1111/jcmm.12667
   Web of Science ®Google Scholar
• Czermak BJ, Sarma V, Pierson CL, et al. Protective effects of C5a blockade in sepsis. Nat Med. 1999;5:788–792. doi:10.1038/10512
   PubMed Web of Science ®Google Scholar
• Laudes IJ, Chu JC, Sikranth S, et al. Anti-c5a ameliorates coagulation/fibrinolytic protein changes in a rat model of sepsis. Am J Pathol. 2002;160(5):1867–1875. doi:10.1016/S0002-9440(10)61133-9
   PubMed Web of Science ®Google Scholar
• Barratt-Due A, Thorgersen EB, Egge K, et al. Combined inhibition of complement C5 and CD14 markedly attenuates inflammation, thrombogenicity, and hemodynamic changes in porcine sepsis. J Immunol. 2013;191(2):819–827. doi:10.4049/jimmunol.1201909
   Web of Science ®Google Scholar
• Skjeflo EW, Sagatun C, Dybwik K, et al. Combined inhibition of complement and CD14 improved outcome in porcine polymicrobial sepsis. Crit Care. 2015;19:415. doi:10.1186/s13054-015-1129-9
   PubMed Web of Science ®Google Scholar
• Sun S, Zhao G, Liu C, et al. Treatment with anti-C5a antibody improves the outcome of H7N9 virus infection in African green monkeys. Clin Infect Dis. 2015;60(4):586–595. doi:10.1093/cid/ciu887
   PubMed Web of Science ®Google Scholar
• Hack CE, Ogilvie AC, Eisele B, Eerenberg AJ, Wagstaff J, Thijs LG. C1-inhibitor substitution therapy in septic shock and in the vascular leak syndrome induced by high doses of interleukin-2. Intensive Care Med. 1993;19(Suppl 1):S19–s28. doi:10.1007/BF01738946
   Google Scholar
• Fronhoffs S, Luyken J, Steuer K, Hansis M, Vetter H, Walger P. The effect of C1-esterase inhibitor in definite and suspected streptococcal toxic shock syndrome. Report of seven patients. Intensive Care Med. 2000;26(10):1566–1570. doi:10.1007/s001340000654
   Web of Science ®Google Scholar
• Igonin AA, Protsenko DN, Galstyan GM, et al. C1-esterase inhibitor infusion increases survival rates for patients with sepsis. Crit Care Med. 2012;40(3):770–777. doi:10.1097/CCM.0b013e318236edb8
   Web of Science ®Google Scholar
• Abe T, Sasaki A, Ueda T, Miyakawa Y, Ochiai H. Complement-mediated thrombotic microangiopathy secondary to sepsis-induced disseminated intravascular coagulation successfully treated with eculizumab: a case report. Medicine (Baltimore). 2017;96(6):e6056. doi:10.1097/MD.0000000000006056
   Web of Science ®Google Scholar
• Urwyler P, Moser S, Charitos P, et al. Treatment of COVID-19 with conestat alfa, a regulator of the complement, contact activation and kallikrein-kinin system. Front Immunol. 2020;11:2072. doi:10.3389/fimmu.2020.02072
   Web of Science ®Google Scholar
• Rambaldi A, Gritti G, Micò MC, et al. Endothelial injury and thrombotic microangiopathy in COVID-19: treatment with the lectin-pathway inhibitor narsoplimab. Immunobiology. 2020;225(6):152001. doi:10.1016/j.imbio.2020.15200
   Web of Science ®Google Scholar
• Mastaglio S, Ruggeri A, Risitano AM, et al. The first case of COVID-19 treated with the complement C3 inhibitor AMY-101. Clin Immunol. 2020;215:108450. doi:10.1016/j.clim.2020.108450
   PubMed Web of Science ®Google Scholar
• Zelek WM, Cole J, Ponsford MJ, et al. Complement inhibition with the C5 blocker LFG316 in severe COVID-19. Am J Respir Crit Care Med. 2020;202(9):1304–1308. doi:10.1164/rccm.202007-2778LE
   PubMed Web of Science ®Google Scholar
• Laurence J, Mulvey JJ, Seshadri M, et al. Anti-complement C5 therapy with eculizumab in three cases of critical COVID-19. Clin Immunol. 2020;219:108555. doi:10.1016/j.clim.2020.108555
   PubMed Web of Science ®Google Scholar
• Diurno F, Numis FG, Porta G, et al. Eculizumab treatment in patients with COVID-19: preliminary results from real life ASL Napoli 2 Nord experience. Eur Rev Med Pharmacol Sci. 2020;24(7):4040–4047. doi:10.26355/eurrev_202004_20875
   PubMed Web of Science ®Google Scholar
• Mastellos DC, Pires da Silva BGP, Fonseca BAL, et al. Complement C3 vs C5 inhibition in severe COVID-19: early clinical findings reveal differential biological efficacy. Clin Immunol. 2020;220:108598. doi:10.1016/j.clim.2020.108598
   PubMed Web of Science ®Google Scholar
• Vlaar APJ, de Bruin S, Busch M, et al. Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial. Lancet Rheumatol. 2020;2(12):e764–e773. doi:10.1016/S2665-9913(20)30341-6
   PubMedGoogle Scholar
• Declercq J, Bosteels C, Van Damme K, et al. Zilucoplan in patients with acute hypoxic respiratory failure due to COVID-19 (ZILU-COV): a structured summary of a study protocol for a randomised controlled trial. Trials. 2020;21(1):934. doi:10.1186/s13063-020-04884-0
   PubMed Web of Science ®Google Scholar
• Wilkinson T, Dixon R, Page C, et al. A multicentre, seamless, phase 2 adaptive randomisation platform study to assess the efficacy and safety of multiple candidate agents for the treatment of COVID-19 in hospitalised patients: a structured summary of a study protocol for a randomised controlled trial. Trials. 2020;21(1):691. doi:10.1186/s13063-020-04584-9
   PubMed Web of Science ®Google Scholar
• CORIMUNO19-ECU: trial evaluating efficacy and safety of eculizumab (Soliris) in patients with COVID-19 infection, nested in the CORIMUNO-19 cohort full text view. Available from: ClinicalTrials.gov. Accessed May 23, 2021.
   Google Scholar
• Kulkarni S, Fisk M, Kostapanos M, et al. Repurposed immunomodulatory drugs for Covid-19 in pre-ICu patients - mulTi-arm therapeutic study in pre-ICU patients admitted with Covid-19 - repurposed drugs (TACTIC-R): a structured summary of a study protocol for a randomised controlled trial. Trials. 2020;21(1):626. doi:10.1186/s13063-020-04535-4
   Web of Science ®Google Scholar
• Ravulizumab and COVID-19 full text view. Available from: ClinicalTrials.gov. Accessed May 23, 2021.
   Google Scholar
• Smith K, Pace A, Ortiz S, Kazani S, Rottinghaus S. A phase 3 open-label, randomized, controlled study to evaluate the efficacy and safety of intravenously administered ravulizumab compared with best supportive care in patients with COVID-19 severe pneumonia, acute lung injury, or acute respiratory distress syndrome: a structured summary of a study protocol for a randomised controlled trial. Trials. 2020;21(1):639. doi:10.1186/s13063-020-04548-z
   PubMed Web of Science ®Google Scholar
• A study of the C3 Inhibitor AMY-101 in patients with ARDS due to COVID-19 (SAVE) - full text view. Available from: ClinicalTrials.gov. Accessed May 23, 2021.
   Google Scholar
• A study of APL-9 in adults with mild to moderate ARDS due to COVID-19 - full text view. Available from: ClinicalTrials.gov. Accessed May 23, 2021.
   Google Scholar
• Study to evaluate the benefit of RUCONEST in improving neurological symptoms in post COVID-19 infection full text view. Available from: ClinicalTrials.gov. Accessed May 23, 2021.
   Google Scholar
• Urwyler P, Charitos P, Moser S, et al. Recombinant human C1 esterase inhibitor (conestat alfa) in the prevention of severe SARS-CoV-2 infection in hospitalized patients with COVID-19: a structured summary of a study protocol for a randomized, parallel-group, open-label, multi-center pilot trial (PROTECT-COVID-19). Trials. 2021;22(1):1. doi:10.1186/s13063-020-04976-x
   Web of Science ®Google Scholar
• Prevention of severe SARS-CoV-2 infection in hospitalized patients with COVID-19 full text view. Available from: ClinicalTrials.gov. Accessed May 23, 2021.
   Google Scholar
• A study of RLS-0071 in patients with acute lung injury due to COVID-19 pneumonia in early respiratory failure full text view. Available from: ClinicalTrials.gov. Accessed May 23, 2021.
   Google Scholar
• I-SPY COVID-19 TRIAL: an adaptive platform trial for critically ill patients full text view. Available from: ClinicalTrials.gov. Accessed May 23, 2021.
   Google Scholar