Pharmacological inhibition of the kinin-kallikrein system in severe COVID-19 – A proof-of-concept study

Mansour, Eli; Palma, André C.; Ulaf, Raisa G.; Ribeiro, Luciana C.; Bernardes, Ana Flávia; Nunes, Thyago A.; Agrela, Marcus Vinicius Rodrigues de; Bombassaro, Bruna; Monfort-Pires, Milena; Camargo, Rafael Ludemann; Araújo, Eliana P.; Brunetti, Natália S; Farias, Alessandro S.; Falcão, Antônio Luis Eiras; Santos, Thiago Martins; Trabasso, Plı́nio; Dertkigil, Rachel P.; Dertkigil, Sérgio; Moretti, Maria Luíza; Velloso, Lı́cio A.

doi:10.1101/2020.08.11.20167353

Cited by 8 publications

(7 citation statements)

References 56 publications

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“…The remaining trial comparisons included: favipiravir versus umifenovir [ 32 ]; umifenovir versus lopinavir-ritonavir [ 39 ]; umifenovir versus standard care [ 39 ]; novaferon versus novaferon plus lopinavir-ritonavir [ 44 ]; novaferon plus lopinavir-ritonavir versus lopinavir-ritonavir [ 44 ]; novaferon versus lopinavir-ritonavir [ 44 ]; alpha lipotic acid versus placebo [ 45 ]; baloxavir marboxil versus favipiravir [ 40 ]; baloxavir marboxil versus standard care [ 40 ]; triple combination of interferon beta-1b plus lopinavir-ritonavir plus ribavirin versus lopinavir-ritonavir [ 37 ]; remdesivir for 5 days versus remdesivir for 10 days [ 36 ]; high-flow nasal oxygenation versus standard bag-valve oxygenation [ 43 ]; hydroxychloroquine versus chloroquine [ 47 ]; chloroquine versus standard care [ 47 ]; high dosage chloroquine diphosphate versus low dosage chloroquine diphosphate [ 49 ]; hydroxychloroquine plus azithromycin versus standard care [ 53 ]; triple combination of darunavir plus cobicistat plus interferon alpha-2b versus interferon alpha-2b [ 60 ]; lopinavir-ritonavir plus interferon alpha versus ribavirin plus interferon alpha [ 60 ]; ribavirin plus lopinavir-ritonavir plus interferon alpha versus ribavirin plus interferon alpha [ 60 ]; ribavirin plus lopinavir-ritonavir plus interferon alpha versus lopinavir-ritonavir plus interferon alpha [ 60 ]; lincomycin versus azithromycin [ 61 ]; 99-mTc-methyl diphosphonate (99mTc-MDP) injection versus standard care [ 62 ]; interferon alpha-2b plus interferon gamma versus interferon alpha-2b [ 63 ]; telmisartan versus standard care [ 65 ]; avifavir 1800/800 versus avifavir 1600/600 [ 66 ]; dexamethasone plus aprepitant versus dexamethasone [ 68 ]; anti-C5a antibody versus standard care [ 69 ]; azvudine versus standard care [ 72 ]; human plasma-derived C1 esterase/kallikrein inhibitor versus standard care [ 71 ]; icatibant acetate versus standard care [ 71 ]; icatibant acetate versus human plasma-derived C1 esterase/kallikrein inhibitor [ 7...…”

Section: Resultsmentioning

confidence: 99%

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

et al. 2021

View full text Add to dashboard Cite

Background COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19. Methods and findings We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias. Meta-analyses showed no evidence of a difference between corticosteroids versus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I2 = 23.1%; eight trials; very low certainty), on serious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached. Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%. All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic intervention effects. Due to lack of data, it was not relevant to perform network meta-analysis or possible to perform individual patient data meta-analyses. Conclusions No evidence-based treatment for COVID-19 currently exists. Very low certainty evidence indicates that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intravenous immunoglobin might reduce the risk of death and serious adverse events; that tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexine might reduce the risk of non-serious adverse events. More trials with low risks of bias and random errors are urgently needed. This review will continuously inform best practice in treatment and clinical research of COVID-19. Systematic review registration PROSPERO CRD42020178787.

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Section: Resultsmentioning

confidence: 99%

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The remaining trial comparisons included: favipiravir versus umifenovir [33]; umifenovir versus lopinavir-ritonavir [40]; umifenovir versus standard care [40]; novaferon versus novaferon plus lopinavir-ritonavir [45]; novaferon plus lopinavir-ritonavir versus lopinavir-ritonavir [45]; novaferon versus lopinavir-ritonavir [45]; alpha lipotic acid versus placebo [46]; baloxavir marboxil versus favipavir [41]; baloxavir marboxil versus standard care [41]; triple combination of interferon beta-1b plus lopinavir-ritonavir plus ribavirin versus lopinavir-ritonavir [38]; remdesivir for 5 days versus remdesivir for 10 days [37]; high-flow nasal oxygenation versus standard bag-valve oxygenation [44]; hydroxychloroquine versus chloroquine [48]; chloroquine versus standard care [48]; high dosage chloroquine diphosphate versus low dosage chloroquine diphosphate [50]; hydroxychloroquine plus azithromycin versus standard care [54]; triple combination of darunavir plus cobicistat plus interferon alpha-2b versus interferon alpha-2b [117]; lopinavir-ritonavir plus interferon alpha versus ribavirin plus interferon alpha [61]; ribavirin plus lopinavir-ritonavir plus interferon alpha versus ribavirin plus interferon alpha [61]; ribavirin plus lopinavir-ritonavir plus interferon alpha versus lopinavir-ritonavir plus interferon alpha [61]; lincomycin versus azithromycin [62];, 99-mTc-methyl diphosphonate (99mTc-MDP) injection versus standard care [63]; interferon alpha-2b plus interferon gamma versus interferon alpha-2b [64]; telmisartan versus standard care [66]; avifavir 1800/800 versus avifavir 1600/600 [67]; dexamethasone plus aprepitant versus dexamethasone [69]; anti-C5a antibody versus standard care [70]; azvudine versus standard care [73]; human plasma-derived C1 esterase/kallikrein inhibitor versus standard care [72]; icatibant acetate versus standard care [72]; icatibant acetate versus human plasma-derived C1 esterase/kallikrein inhibitor [72]; pulmonary rehabilitation program versus isolation at home [71]; auxora (calcium release-activated calcium channel inhibitors) versus standard care [74]; umbilical cord stem cell infusion versus standard care [75]; vitamin C versus placebo [76]; sofosbuvir plus daclatasvir versus standard care [80]; sofosbuvir plus daclatasvir plus ribavirin versus hydroxychloroquine plus lopinavir-ritonavir with or without ribavirin [79]; interferon beta-1b versus standard care [81]; calcifediol versus standard care [84]; recombinant human granulocyte colony–stimulating factor versus standard care [85]; intravenous and/or nebulized electrolyzed saline w...…”

Section: Resultsmentioning

confidence: 99%

Interventions for treatment of COVID-19: second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

Juul

Feinberg

Siddiqui

et al. 2020

Preprint

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BackgroundCOVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19.Methods and findingsWe planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology.We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias.Meta-analyses showed no evidence of a difference between corticosteroids versus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I2 = 23.1%; eight trials; very low certainty), on serious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached.Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events.Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects.Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects.Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexidine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects.Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%.Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%.All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic intervention effects. Due to lack of data, it was not relevant to perform network meta-analysis or possible to perform individual patient data meta-analyses.ConclusionsNo evidence-based treatment for COVID-19 currently exists. Very low certainty evidence indicates that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intraveneous immunoglobin might reduce the risk of death and serious adverse events; that tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexidine might reduce the risk of non-serious adverse events. More trials with low risks of bias and random errors are urgently needed. This review will continuously inform best practice in treatment and clinical research of COVID-19.Systematic review registration PROSPERO CRD42020178787Author summaryWhy was this study done?Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread rapidly worldwide, causing an international outbreak of the corona virus disease 2019 (COVID-19).There is a need for a living systematic review evaluating the beneficial and harmful effects of all possible interventions for treatment of COVID-19.What did the researchers do and find?We conducted the second edition of our living systematic review with meta-analyses and Trial sequential analyses to compare the effects of all treatment interventions for COVID-19.Very low certainty evidence indicated that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intraveneous immunoglobin might reduce the risk of death and serious adverse events; that tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexidine might reduce the risk of non-serious adverse events.Nine single trials showed statistically significant results on our predefined outcomes but were underpowered to confirm or reject realistic intervention effects.None of the remaining trials showed evidence of a difference of the experimental interventions on our predefined outcomes.What do these findings mean?No evidence-based treatment for COVID-19 currently existsMore high quality, low risk of bias randomized clinical trials are urgently needed.

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“…Az idős személyekben -különösen, akiknél súlyos athe rosclerosis alakul ki hypertonia vagy diabetes következtében -már létrejönnek az érfalban a XII-es faktor aktiválódásának feltételei: (A) az endothelium sejtjei ká-rosodnak, felszínük elveszti a negatív töltésű molekuláit; (B) az elasztikus rostok eltűnnek a subendotheliumrétegből; (C) a simaizomréteg integritása megszűnik; (D) az érfal kollagénrostokkal telítődik [9], merevvé válik, artériás merevség (stiffness) alakul ki [10]; (E) a sérült endotheliumfelszínen aktiválódik a XII-es faktor (XIIa), ami a trombinképzés útján tovább növeli a párhuzamosan működő extrinszik út fibrinmennyiségét, emellett a ------------ [11][12][13].…”

Section: Eredményekunclassified

“…A COVID-19 vonatkozásában ez új megközelítésnek számít, ugyanakkor hasonló mechanizmus már leírásra került korábban a haemorrhagiás lázzal és renalis szindrómával járó hantavírus-fertőzésben [15]. A COVID-19-fertőzésekben kialakuló "bradikininvihar" lecsendesítésének leggyorsabban kipróbálható új oki terápiáját a különböző C1INH-készítmények és bradikininantagonista gyógyszerek jelenthetik [11][12][13].…”

Section: Megbeszélésunclassified

See 1 more Smart Citation

A felületaktivált XII-es véralvadási faktor életkortól függő lehetséges szerepe a „bradikininvihar” kialakításában COVID–19-betegekben

Sipka

Tóth

2020

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Összefoglaló. Bevezetés: Egy új, számítógép által segített betegminta-asszociációs analízis eredménye szerint a COVID–19 tüneteinek kialakításában kiemelt tényezőként jelenik meg a bradikinin. Eszerint a bradikinin lebontása lelassul az angiotenzinkonvertáló enzim aktivitásának csökkenése miatt, ami jelentősen megemelkedő bradikininszinthez vezet a tüdőben. Nem merült fel azonban a véralvadási faktorok lehetséges szerepe a „bradikininviharban”, annak ellenére, hogy az idősebb cardiovascularis betegekben aktiválódó XII-es faktor és a C1-észteráz-inhibitor (C1INH) alacsony szintje nagy mennyiségű bradikinin képződéséhez vezethet. Módszer: Átfogó irodalmi áttekintés. Eredmények: 1) A vírus által fertőzött, sérült endotheliumsejtek felülete az a hely, amellyel érintkezve elindulhat a XII-es véralvadási faktor aktivációja – ez serkenti a prekallikrein/kallikrein/kinin rendszert, és bradikininképződést okoz. Ez a folyamat megtörténik a súlyos vese- és tüdőkárosodást okozó hantavírus-fertőzésekben. 2) Idős betegekben az atherosclerosis miatt többszörösen sérült, merev, „stiff” erek endotheliumfelszínein jóval magasabb lehet a XII-es faktor kontakt úton történő aktivációja, mint a fiatal egyének ereiben. Ez a tény egyik oka lehet az idős, cardiovascularis betegek körében tapasztalt magasabb halálozásnak. Következtetés: Az aktivált XII-es véralvadási faktor célzott gátlása újabb gyógyítási lehetőség lehet a SARS-CoV-2-fertőzött idős betegekben. Jelenleg már hatásosnak bizonyult a bradikininképzést gátló C1INH-nak, továbbá a bradikininreceptor-gátlóknak az adása is. Orv Hetil. 2020; 161(50): 2099–2103. Summary. Introduction: Bradykinin was implicated in a new complex model of pathomechanism leading to the symptoms of COVID-19 created by a computer-assisted association analysis. According to this model, the decrease in angiotensin-converting enzyme expression leads to impaired bradykinin elimination and subsequent enrichment in the lungs. However, there is no mentioning of the importance of blood coagulation factor XII in increased bradykinin production, in spite of its age-dependent activation and the lower level of C1-esterase inhibitor (C1INH). Activated factor XII may be an important contributor to the “bradykinin storm” in elder cardiovascular patients. Method: Literature review. Results: 1) Activation of the coagulation factor XII on the surface of SARS-CoV-2 infected endothelial cells may trigger the prekallikrein/kallikrein/kinin system producing bradykinin. Such process is taking place in hantavirus infections causing severe lung and kidney damages. 2) The endothelial system is dysregulated in elderly patients, resulting in potentially higher factor XII activities on the surface of damaged endothelial cells in the stiffened arteries. This can contribute to the higher mortality rates in the elderly. Conclusion: The targeted inhibition of activated blood coagulation factor XII may represent a new therapeutic target for COVID-19, especially for elder patients. Recently, beneficial results have already been observed by the clinical applications of recombinant C1INH and bradykinin receptor antagonists. Orv Hetil. 2020; 161(50): 2099–2103.

show abstract

Pharmacological inhibition of the kinin-kallikrein system in severe COVID-19 – A proof-of-concept study

Cited by 8 publications

References 56 publications

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

Interventions for treatment of COVID-19: second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

A felületaktivált XII-es véralvadási faktor életkortól függő lehetséges szerepe a „bradikininvihar” kialakításában COVID–19-betegekben

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