Adjunctive Recombinant Human Plasma Gelsolin for Severe Coronavirus Disease 2019 Pneumonia
Mark J Dinubile, Sandra Parra, Antoni Castro Salomó, Susan L Levinson
Open Forum Infectious Diseases, doi:10.1093/ofid/ofac357
Background. Excessive inflammation contributes to the morbidity and mortality of severe coronavirus disease 2019 (COVID-19) pneumonia. Recombinant human plasma gelsolin (rhu-pGSN) improves disease outcomes in diverse experimental models of infectious and noninfectious inflammation. Methods. In a blinded, randomized study, 61 subjects with documented COVID-19 pneumonia having a World Health Organization (WHO) Severity Score of 4 to 6 and evidence of a hyperinflammatory state were treated with standard care and either adjunctive rhu-pGSN 12 mg/kg or an equal volume of saline placebo given intravenously at entry, 12 hours, and 36 hours. The prespecified coprimary outcomes were survival without major respiratory, hemodynamic, or renal support on Day 14 and the incidence of serious adverse events (SAEs) during the 90-day study period. Results. All subjects receiving ≥1 dose of study drug were analyzed. Fifty-four of 61 subjects (88.5%) were WHO severity level 4 at entry. The proportions of subjects alive without support on Day 14 were 25 of 30 rhu-pGSN recipients (83.3%) and 27 of 31 placebo recipients (87.1%). Over the duration of the study, WHO Severity Scores improved similarly in both treatment groups. No statistically significant differences were observed between treatment groups at any time point examined. Two subjects died in each group. Numerically fewer subjects in the rhu-pGSN group had SAEs (5 subjects; 16.7%) or ≥ Grade 3 adverse events (5 subjects; 16.7%) than in the placebo group (8 subjects [25.8%] and 9 subjects [29.0%], respectively), mostly involving the lungs. Three rhu-pGSN recipients (10.0%) were intubated compared to 6 placebo recipients (19.4%). Conclusions. Overall, subjects in this study did well irrespective of treatment arm. When added to dexamethasone and remdesivir, no definitive benefit was demonstrated for rhu-pGSN relative to placebo. Safety signals were not identified after the administration of 3 doses of 12 mg/kg rhu-pGSN over 36 hours. The frequencies of SAEs and intubation were numerically fewer in the rhu-pGSN group compared with placebo.
DISCUSSION In subjects with severe COVID-19 pneumonia requiring oxygen supplementation, our small, randomized, double-blinded trial did not demonstrate a benefit of rhu-pGSN over placebo when added to standard of care. Plasma gelsolin plays a central regulatory role in diverse inflammatory pathways (Supplemental Materials: Clinical Study Report) [3, 34, 35] . When appropriately timed, a dual-pronged attack on COVID-19 reducing the inciting virus early (with remdesivir or other antiviral agents) and moderating the later exuberant inflammatory reaction might theoretically synergize in shutting down COVID-19 progression better than either modality alone. Repletion of pGSN could effectively block unbridled and injurious immune activation without inducing undesired side-effects or dangerous immunosuppression. No unexpected safety signals were apparent during this trial with the incidence of SAEs numerically (but not statistically) lower in rhu-pGSN than placebo recipients. To establish the safety profile of rhu-pGSN without confounding comorbidities, we had conducted our first dose-escalation study in 33 mildly ill patients
Supplementary Data Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. Author contributions. All..
References
Abers, Delmonte, Ricotta, An immune-based biomarker signature is associated with mortality in COVID-19 patients, JCI Insight
Brodin, Immune determinants of COVID-19 disease presentation and severity, Nat Med
Bucki, Byfield, Kulakowska, Extracellular gelsolin binds lipoteichoic acid and modulates cellular response to proinflammatory bacterial wall components, J Immunol
Bucki, Georges, Espinassous, Inactivation of endotoxin by human plasma gelsolin, Biochemistry
Bucki, Kułakowska, Byfield, Plasma gelsolin modulates cellular response to sphingosine 1-phosphate, Am J Physiol Cell Physiol
Calabrese, Cytokine storm and the prospects for immunotherapy with COVID-19, Cleve Clin J Med
Dinsdale, Hazeldine, Tarrah, Dysregulation of the actin scavenging system and inhibition of DNase activity following severe thermal injury, Br J Surg
Dinubile, Plasma gelsolin: in search of its raison d'être. Focus on "Modifications of cellular responses to lysophosphatidic acid and platelet-activating factor by plasma gelsolin, Am J Physiol Cell Physiol
Erukhimov, Tang, Johnson, Actin-containing sera from patients with adult respiratory distress syndrome are toxic to sheep pulmonary endothelial cells, Am J Respir Crit Care Med
Goetzl, Lee, Azuma, Stossel, Turck et al., Gelsolin binding and cellular presentation of lysophosphatidic acid, J Biol Chem
Goletti, Cantini, Baricitinib therapy in COVID-19 pneumonia-an unmet need fulfilled, N Engl J Med
Group; Horby, Lim, Dexamethasone in hospitalized patients with COVID-19, N Engl J Med
Haddad, Harper, Guoth, Pietra, Sanger, Angiopathic consequences of saturating the plasma scavenger system for actin, Proc Natl Acad Sci U S A
Hu, Li, Li, The value of decreased plasma gelsolin levels in patients with systemic lupus erythematosus and rheumatoid arthritis in diagnosis and disease activity evaluation, Lupus
Huang, Yao, Li, Reduction of plasma gelsolin levels correlates with development of multiple organ dysfunction syndrome and fatal outcome in burn patients, PLoS One
Janmey, Lamb, Ezzell, Hvidt, Lind, Effects of actin filaments on fibrin clot structure and lysis, Blood
Lazarides, Lindberg, Actin is the naturally occurring inhibitor of deoxyribonuclease I, Proc Natl Acad Sci U S A
Lee, Drager, Stossel, Moore, Rogers, Relationship of plasma gelsolin levels to outcomes in critically ill surgical patients, Ann Surg
Lee, Galbraith, The extracellular actin-scavenger system and actin toxicity, N Engl J Med
Lee, Patel, Christiani, Bajwa, Stossel et al., Plasma gelsolin depletion and circulating actin in sepsis-A pilot study, PLoS One
Lind, Smith, Janmey, Stossel, Role of plasma gelsolin and the vitamin D-binding protein in clearing actin from the circulation, J Clin Invest
Messner, Demichev, Wendisch, Ultra-high-throughput clinical proteomics reveals classifiers of COVID-19 infection, Cell Syst
Middleton, He, Denorme, Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome, Blood
Moore, June, Cytokine release syndrome in severe COVID-19, Science
Mounzer, Moncure, Smith, Dinubile, Relationship of admission plasma gelsolin levels to clinical outcomes in patients after major trauma, Am J Respir Crit Care Med
Nag, Larsson, Robinson, Burtnick, Gelsolin: the tail of a molecular gymnast, Cytoskeleton
Ordija, Chiou, Yang, Free actin impairs macrophage bacterial defenses via scavenger receptor MARCO interaction with reversal by plasma gelsolin, Am J Physiol Lung Cell Mol Physiol
Osborn, Dahlgren, Hartwig, Stossel, Modifications of cellular responses to lysophosphatidic acid and platelet-activating factor by plasma gelsolin, Am J Physiol Cell Physiol
Overmyer, Shishkova, Miller, Large-scale multi-omic analysis of COVID-19 severity, Cell Syst
Padilla, Polotskaya, Fernández, Survival benefit of remdesivir in hospitalized COVID-19 patients with high SARS-CoV-2 viral loads and low-grade systemic inflammation, J Antimicrob Chemother
Parra, Heras, Herrero, Gelsolin: a new biomarker of disease activity in SLE patients associated with HDL-c, Rheumatology
Piktel, Levental, Durnaś, Janmey, Bucki, Plasma gelsolin: indicator of inflammation and its potential as a diagnostic tool and therapeutic target, Int J Mol Sci
Ryabkova, Churilov, Shoenfeld, Influenza infection, SARS, MERS and COVID-19: cytokine storm-the common denominator and the lessons to be learned, Clin Immunol
Self, Wunderink, Dinubile, Low admission plasma gelsolin concentrations identify community-acquired pneumonia patients at high risk for severe outcomes, Clin Infect Dis
Sharma, Goswami, Mandal, Guha, Willard et al., Quorum sensing by gelsolin regulates programmed cell death 4 expression and a densitydependent phenotype in macrophages, J Immunol
Tannous, Levinson, Bolognese, Opal, Dinubile, Safety and pharmacokinetics of recombinant human plasma gelsolin in patients hospitalized for nonsevere community-acquired pneumonia, Antimicrob Agents Chemother
Yang, Bedugnis, Levinson, Delayed administration of recombinant plasma gelsolin improves survival in a murine model of severe influenza, Res
Yang, Chiou, Stossel, Kobzik, Plasma gelsolin improves lung host defense against pneumonia by enhancing macrophage NOS3 function, Am J Physiol Lung Cell Mol Physiol
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"abstract": "<jats:title>Abstract</jats:title>\n <jats:sec>\n <jats:title>Background</jats:title>\n <jats:p>Excessive inflammation contributes to the morbidity and mortality of severe coronavirus disease 2019 (COVID-19) pneumonia. Recombinant human plasma gelsolin (rhu-pGSN) improves disease outcomes in diverse experimental models of infectious and noninfectious inflammation.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>In a blinded, randomized study, 61 subjects with documented COVID-19 pneumonia having a World Health Organization (WHO) Severity Score of 4 to 6 and evidence of a hyperinflammatory state were treated with standard care and either adjunctive rhu-pGSN 12 mg/kg or an equal volume of saline placebo given intravenously at entry, 12 hours, and 36 hours. The prespecified coprimary outcomes were survival without major respiratory, hemodynamic, or renal support on Day 14 and the incidence of serious adverse events (SAEs) during the 90-day study period.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>All subjects receiving ≥1 dose of study drug were analyzed. Fifty-four of 61 subjects (88.5%) were WHO severity level 4 at entry. The proportions of subjects alive without support on Day 14 were 25 of 30 rhu-pGSN recipients (83.3%) and 27 of 31 placebo recipients (87.1%). Over the duration of the study, WHO Severity Scores improved similarly in both treatment groups. No statistically significant differences were observed between treatment groups at any time point examined. Two subjects died in each group. Numerically fewer subjects in the rhu-pGSN group had SAEs (5 subjects; 16.7%) or ≥ Grade 3 adverse events (5 subjects; 16.7%) than in the placebo group (8 subjects [25.8%] and 9 subjects [29.0%], respectively), mostly involving the lungs. Three rhu-pGSN recipients (10.0%) were intubated compared to 6 placebo recipients (19.4%).</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusions</jats:title>\n <jats:p>Overall, subjects in this study did well irrespective of treatment arm. When added to dexamethasone and remdesivir, no definitive benefit was demonstrated for rhu-pGSN relative to placebo. Safety signals were not identified after the administration of 3 doses of 12 mg/kg rhu-pGSN over 36 hours. The frequencies of SAEs and intubation were numerically fewer in the rhu-pGSN group compared with placebo.</jats:p>\n </jats:sec>",
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"volume": "326",
"year": "1992"
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"DOI": "10.1152/ajpcell.00007.2007",
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"volume": "292",
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"journal-title": "J Clin Invest",
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"volume": "78",
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"journal-title": "Blood",
"key": "2022080218335118100_ofac357-B5",
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"author": "Yang",
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"first-page": "L11",
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"volume": "309",
"year": "2015"
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"DOI": "10.1016/j.clim.2020.108652",
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"volume": "223",
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