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1.
Crit Care ; 26(1): 34, 2022 02 05.
Article in English | MEDLINE | ID: covidwho-1706840

ABSTRACT

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has become an established rescue therapy for severe acute respiratory distress syndrome (ARDS) in several etiologies including influenza A H1N1 pneumonia. The benefit of receiving ECMO in coronavirus disease 2019 (COVID-19) is still uncertain. The aim of this analysis was to compare the outcome of patients who received veno-venous ECMO for COVID-19 and Influenza A H1N1 associated ARDS. METHODS: This was a multicenter retrospective cohort study including adults with ARDS, receiving ECMO for COVID-19 and influenza A H1N1 pneumonia between 2009 and 2021 in seven Italian ICU. The primary outcome was any-cause mortality at 60 days after ECMO initiation. We used a multivariable Cox model to estimate the difference in mortality accounting for patients' characteristics and treatment factors before ECMO was started. Secondary outcomes were mortality at 90 days, ICU and hospital length of stay and ECMO associated complications. RESULTS: Data from 308 patients with COVID-19 (N = 146) and H1N1 (N = 162) associated ARDS who had received ECMO support were included. The estimated cumulative mortality at 60 days after initiating ECMO was higher in COVID-19 (46%) than H1N1 (27%) patients (hazard ratio 1.76, 95% CI 1.17-2.46). When adjusting for confounders, specifically age and hospital length of stay before ECMO support, the hazard ratio decreased to 1.39, 95% CI 0.78-2.47. ICU and hospital length of stay, duration of ECMO and invasive mechanical ventilation and ECMO-associated hemorrhagic complications were higher in COVID-19 than H1N1 patients. CONCLUSION: In patients with ARDS who received ECMO, the observed unadjusted 60-day mortality was higher in cases of COVID-19 than H1N1 pneumonia. This difference in mortality was not significant after multivariable adjustment; older age and longer hospital length of stay before ECMO emerged as important covariates that could explain the observed difference. TRIAL REGISTRATION NUMBER: NCT05080933 , retrospectively registered.


Subject(s)
COVID-19 , Extracorporeal Membrane Oxygenation , Influenza A Virus, H1N1 Subtype , Influenza, Human , Respiratory Distress Syndrome , Adult , Aged , Humans , Influenza, Human/complications , Influenza, Human/therapy , Respiratory Distress Syndrome/therapy , Retrospective Studies , SARS-CoV-2
2.
PLoS One ; 16(12): e0261113, 2021.
Article in English | MEDLINE | ID: covidwho-1637108

ABSTRACT

BACKGROUND: Complement activation contributes to lung dysfunction in coronavirus disease 2019 (COVID-19). We assessed whether C5 blockade with eculizumab could improve disease outcome. METHODS: In this single-centre, academic, unblinded study two 900 mg eculizumab doses were added-on standard therapy in ten COVID-19 patients admitted from February 2020 to April 2020 and receiving Continuous-Positive-Airway-Pressure (CPAP) ventilator support from ≤24 hours. We compared their outcomes with those of 65 contemporary similar controls. Primary outcome was respiratory rate at one week of ventilator support. Secondary outcomes included the combined endpoint of mortality and discharge with chronic complications. RESULTS: Baseline characteristics of eculizumab-treated patients and controls were similar. At baseline, sC5b-9 levels, ex vivo C5b-9 and thrombi deposition were increased. Ex vivo tests normalised in eculizumab-treated patients, but not in controls. In eculizumab-treated patients respiratory rate decreased from 26.8±7.3 breaths/min at baseline to 20.3±3.8 and 18.0±4.8 breaths/min at one and two weeks, respectively (p<0.05 for both), but did not change in controls. Between-group changes differed significantly at both time-points (p<0.01). Changes in respiratory rate correlated with concomitant changes in ex vivo C5b-9 deposits at one (rs = 0.706, p = 0.010) and two (rs = 0.751, p = 0.032) weeks. Over a median (IQR) period of 47.0 (14.0-121.0) days, four eculizumab-treated patients died or had chronic complications versus 52 controls [HRCrude (95% CI): 0.26 (0.09-0.72), p = 0.010]. Between-group difference was significant even after adjustment for age, sex and baseline serum creatinine [HRAdjusted (95% CI): 0.30 (0.10-0.84), p = 0.023]. Six patients and 13 controls were discharged without complications [HRCrude (95% CI): 2.88 (1.08-7.70), p = 0.035]. Eculizumab was tolerated well. The main study limitations were the relatively small sample size and the non-randomised design. CONCLUSIONS: In patients with severe COVID-19, eculizumab safely improved respiratory dysfunction and decreased the combined endpoint of mortality and discharge with chronic complications. Findings need confirmation in randomised controlled trials.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/therapy , Continuous Positive Airway Pressure , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , COVID-19/drug therapy , COVID-19/mortality , COVID-19/physiopathology , Case-Control Studies , Complement Membrane Attack Complex/analysis , Female , Humans , Male , Middle Aged , Retrospective Studies , Thrombosis/drug therapy , Treatment Outcome
3.
TH Open ; 5(3): e253-e263, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1483194

ABSTRACT

Introduction Endothelial damage and hypercoagulability are major players behind the hemostatic derangement of SARS-CoV-2 infection. Aim In this prospective study we assessed endothelial and inflammatory biomarkers in a cohort of COVID-19 patients, aiming to identify predictive factors of in-hospital mortality. Methods COVID-19 patients hospitalized in intensive care (ICU) and non-ICU units at 2 Bergamo (Italy) hospitals from March 23 to May 30, 2020, were enrolled. Markers of endothelium activation including von-Willebrand factor (vWF), soluble thrombomodulin (sTM), and fibrinolytic proteins (t-PA and PAI-1) were measured. Additionally, D-dimer, Fibrinogen, FVIII, nucleosomes, C reactive protein (CRP) and procalcitonin were assessed. Results Sixty-three (45 ICU, and 18 non-ICU) patients, with a median age of 62 years were analyzed. Increased plasma levels of D-dimer, FVIII, fibrinogen, nucleosomes, CRP, and procalcitonin were observed in the whole cohort. Extremely elevated vWF levels characterized all patients (highest values in ICU-subjects). After a median time of 30 days, death occurred in 13 (21%) patients. By multivariable analysis, vWF-activity, neutrophil-count and PaO2/FiO2 were significantly associated with death. Using these variables, a linear score with 3-risk groups was generated that provided a cumulative incidence of death of 0% in the low-, 32% in the intermediate-, and 78% in the high-risk group. Conclusions COVID-19-induced hemostatic abnormalities are exacerbated by the severity of the disease and strongly correlate with the inflammatory status, underlying the link between coagulation, endothelial activation, and inflammation. Our study provides evidence for a role of vWF, together with neutrophils and PaO2/FiO2, as a significant predictor of in-hospital mortality by SARSCoV-2 infection.

4.
JAMA ; 323(16): 1574-1581, 2020 04 28.
Article in English | MEDLINE | ID: covidwho-1453471

ABSTRACT

Importance: In December 2019, a novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) emerged in China and has spread globally, creating a pandemic. Information about the clinical characteristics of infected patients who require intensive care is limited. Objective: To characterize patients with coronavirus disease 2019 (COVID-19) requiring treatment in an intensive care unit (ICU) in the Lombardy region of Italy. Design, Setting, and Participants: Retrospective case series of 1591 consecutive patients with laboratory-confirmed COVID-19 referred for ICU admission to the coordinator center (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy) of the COVID-19 Lombardy ICU Network and treated at one of the ICUs of the 72 hospitals in this network between February 20 and March 18, 2020. Date of final follow-up was March 25, 2020. Exposures: SARS-CoV-2 infection confirmed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay of nasal and pharyngeal swabs. Main Outcomes and Measures: Demographic and clinical data were collected, including data on clinical management, respiratory failure, and patient mortality. Data were recorded by the coordinator center on an electronic worksheet during telephone calls by the staff of the COVID-19 Lombardy ICU Network. Results: Of the 1591 patients included in the study, the median (IQR) age was 63 (56-70) years and 1304 (82%) were male. Of the 1043 patients with available data, 709 (68%) had at least 1 comorbidity and 509 (49%) had hypertension. Among 1300 patients with available respiratory support data, 1287 (99% [95% CI, 98%-99%]) needed respiratory support, including 1150 (88% [95% CI, 87%-90%]) who received mechanical ventilation and 137 (11% [95% CI, 9%-12%]) who received noninvasive ventilation. The median positive end-expiratory pressure (PEEP) was 14 (IQR, 12-16) cm H2O, and Fio2 was greater than 50% in 89% of patients. The median Pao2/Fio2 was 160 (IQR, 114-220). The median PEEP level was not different between younger patients (n = 503 aged ≤63 years) and older patients (n = 514 aged ≥64 years) (14 [IQR, 12-15] vs 14 [IQR, 12-16] cm H2O, respectively; median difference, 0 [95% CI, 0-0]; P = .94). Median Fio2 was lower in younger patients: 60% (IQR, 50%-80%) vs 70% (IQR, 50%-80%) (median difference, -10% [95% CI, -14% to 6%]; P = .006), and median Pao2/Fio2 was higher in younger patients: 163.5 (IQR, 120-230) vs 156 (IQR, 110-205) (median difference, 7 [95% CI, -8 to 22]; P = .02). Patients with hypertension (n = 509) were older than those without hypertension (n = 526) (median [IQR] age, 66 years [60-72] vs 62 years [54-68]; P < .001) and had lower Pao2/Fio2 (median [IQR], 146 [105-214] vs 173 [120-222]; median difference, -27 [95% CI, -42 to -12]; P = .005). Among the 1581 patients with ICU disposition data available as of March 25, 2020, 920 patients (58% [95% CI, 56%-61%]) were still in the ICU, 256 (16% [95% CI, 14%-18%]) were discharged from the ICU, and 405 (26% [95% CI, 23%-28%]) had died in the ICU. Older patients (n = 786; age ≥64 years) had higher mortality than younger patients (n = 795; age ≤63 years) (36% vs 15%; difference, 21% [95% CI, 17%-26%]; P < .001). Conclusions and Relevance: In this case series of critically ill patients with laboratory-confirmed COVID-19 admitted to ICUs in Lombardy, Italy, the majority were older men, a large proportion required mechanical ventilation and high levels of PEEP, and ICU mortality was 26%.


Subject(s)
Betacoronavirus , Coronavirus Infections/epidemiology , Critical Care/statistics & numerical data , Hospital Mortality , Intensive Care Units/statistics & numerical data , Pneumonia, Viral/epidemiology , Positive-Pressure Respiration/statistics & numerical data , Adolescent , Adult , Age Distribution , Aged , Aged, 80 and over , COVID-19 , Comorbidity , Coronavirus Infections/mortality , Coronavirus Infections/physiopathology , Coronavirus Infections/therapy , Critical Illness/therapy , Female , Hospitalization , Humans , Italy/epidemiology , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Pneumonia, Viral/physiopathology , Pneumonia, Viral/therapy , Respiration, Artificial , Retrospective Studies , SARS-CoV-2 , Sex Distribution , Young Adult
5.
Blood ; 136(Supplement 1):36-36, 2020.
Article in English | PMC | ID: covidwho-1338963

ABSTRACT

INTRODUCTION The occurrence of a hypercoagulable state in hospitalized COVID-19 patients is supported by studies conducted with routine coagulation tests, including plasma D-dimer and fibrinogen, and platelet count.AIM In this study we performed an extensive characterization of the hemostatic alterations by both global and specific assays in a cohort of 78 patients hospitalized for COVID-19. The aims were to: 1) clarify mechanisms underlying the coagulopathy, and 2) identify predictive factors of disease severity and thrombotic events (i.e. deep vein thrombosis [DVT], pulmonary embolism [PE] or arterial thromboembolism [ATE]).METHODS COVID-19 patients admitted to the Hospital Papa Giovanni XXIII in Bergamo, Italy, from March 23 to May 30, 2020, were enrolled prospectively, providing informed consent. As a global assay, thromboelastometry (ROTEM) was performed in whole blood by EXTEM, INTEM, and FIBTEM tests. Specific assays included plasma levels of intrinsic and extrinsic pathway coagulation factors, von Willebrand factor (vWF) antigen and activity, anticoagulant proteins (i.e. protein C [PC], free-protein S [PS], and antithrombin [AT]), fibrinolytic proteins (i.e. tissue plasminogen activator [t-PA], and inhibitor [PAI-1]), and hypercoagulation biomarkers (i.e. prothrombin fragment 1+2 [F1+2], and D-dimer). In addition, biomarkers of immunoinflammation (i.e. neutrophil extracellular traps [NETs], CRP and procalcitonin) were measured. Occurrence of thrombotic events and death were monitored during follow up.RESULTS 78 patients (56M/22F), median age 62.7 years (25-87), were analyzed. According to disease severity, 45 were ICU, and 33 non-ICU patients. Sixty-three of them were on thromboprophylaxis. Global hemostasis analysis by ROTEM showed a prothrombotic profile in patients compared to controls, with a significantly shorter clot formation time (CFT), and increased maximum clot firmness (MCF), which were significantly greater in the ICU vs non-ICU patients. The occurrence of an 'in vivo' hypercoagulable state was confirmed by increased plasma levels of F1+2 and D-dimer, with the highest values of D-dimer in the ICU subjects. Hypercoagulability, rather than factors' consumption, was also shown by the findings of significantly higher plasma procoagulant factors V, VIII, IX and fibrinogen in ICU compared to non-ICU patients (p<0.001). Endothelium activation was shown by extremely elevated vWF antigen and activity levels in all patients (highest values in ICU subjects). Moreover, the concentrations of fibrinolytic proteins, t-PA, and its inhibitor PAI-1, were elevated (p<0.01) in patients compared to normal controls, without difference between ICU and non-ICU subjects. Finally, the inflammatory parameters' analysis in the ICU group demonstrated significantly increased plasma levels of NETs, CRP, and procalcitonin, compared to non-ICU patients. Of note, NETs levels significantly (p<0.02) correlated with vWF, D-dimer and t-PA, while CRP and procalcitonin inversely correlated with anticoagulant PC.After a median time of 8.8 days, 19 (24%) patients experienced thrombosis (3 DVT, 8 PE, 8 ATE). Thirteen (17%) patients from total population died after a median time of 33 days of hospitalization. Baseline D-dimer and t-PA levels were significantly higher in patients developing VTE, while baseline FVIII, vWF and D-dimer levels were greater in subjects who died during follow-up. By Cox analysis, high D-dimer and younger age were significantly associated with mortality.CONCLUSIONS Our study provides for the first time an extensive overview of the hypercoagulable state induced by SARSCoV-2 infection, demonstrating alterations in all of the different hemostatic compartments analyzed. The viral infection-induced hemostatic abnormalities are exacerbated by the severity of the disease and strongly correlate with the proinflammatory status, demonstrating the link between coagulation and inflammation. This link is further supported by the clear correlation found between NETosis and markers of endothelial and blood clotting act vation. Finally, these data add evidence to the role of D-dimer as a significant predictor of intra-hospital mortality.

6.
Front Med (Lausanne) ; 7: 607786, 2020.
Article in English | MEDLINE | ID: covidwho-1069727

ABSTRACT

Background: Most respiratory viruses show pronounced seasonality, but for SARS-CoV-2, this still needs to be documented. Methods: We examined the disease progression of COVID-19 in 6,914 patients admitted to hospitals in Europe and China. In addition, we evaluated progress of disease symptoms in 37,187 individuals reporting symptoms into the COVID Symptom Study application. Findings: Meta-analysis of the mortality risk in seven European hospitals estimated odds ratios per 1-day increase in the admission date to be 0.981 (0.973-0.988, p < 0.001) and per increase in ambient temperature of 1°C to be 0.854 (0.773-0.944, p = 0.007). Statistically significant decreases of comparable magnitude in median hospital stay, probability of transfer to the intensive care unit, and need for mechanical ventilation were also observed in most, but not all hospitals. The analysis of individually reported symptoms of 37,187 individuals in the UK also showed the decrease in symptom duration and disease severity with time. Interpretation: Severity of COVID-19 in Europe decreased significantly between March and May and the seasonality of COVID-19 is the most likely explanation.

7.
PLoS One ; 16(1): e0245281, 2021.
Article in English | MEDLINE | ID: covidwho-1067411

ABSTRACT

BACKGROUNDS: Validated tools for predicting individual in-hospital mortality of COVID-19 are lacking. We aimed to develop and to validate a simple clinical prediction rule for early identification of in-hospital mortality of patients with COVID-19. METHODS AND FINDINGS: We enrolled 2191 consecutive hospitalized patients with COVID-19 from three Italian dedicated units (derivation cohort: 1810 consecutive patients from Bergamo and Pavia units; validation cohort: 381 consecutive patients from Rome unit). The outcome was in-hospital mortality. Fine and Gray competing risks multivariate model (with discharge as a competing event) was used to develop a prediction rule for in-hospital mortality. Discrimination and calibration were assessed by the area under the receiver operating characteristic curve (AUC) and by Brier score in both the derivation and validation cohorts. Seven variables were independent risk factors for in-hospital mortality: age (Hazard Ratio [HR] 1.08, 95% Confidence Interval [CI] 1.07-1.09), male sex (HR 1.62, 95%CI 1.30-2.00), duration of symptoms before hospital admission <10 days (HR 1.72, 95%CI 1.39-2.12), diabetes (HR 1.21, 95%CI 1.02-1.45), coronary heart disease (HR 1.40 95% CI 1.09-1.80), chronic liver disease (HR 1.78, 95%CI 1.16-2.72), and lactate dehydrogenase levels at admission (HR 1.0003, 95%CI 1.0002-1.0005). The AUC was 0.822 (95%CI 0.722-0.922) in the derivation cohort and 0.820 (95%CI 0.724-0.920) in the validation cohort with good calibration. The prediction rule is freely available as a web-app (COVID-CALC: https://sites.google.com/community.unipa.it/covid-19riskpredictions/c19-rp). CONCLUSIONS: A validated simple clinical prediction rule can promptly and accurately assess the risk for in-hospital mortality, improving triage and the management of patients with COVID-19.


Subject(s)
COVID-19/mortality , Adult , Aged , Aged, 80 and over , COVID-19/epidemiology , Cohort Studies , Female , Hospital Mortality , Hospitalization/statistics & numerical data , Humans , Italy/epidemiology , Male , Middle Aged , Mobile Applications , ROC Curve , Retrospective Studies , Risk Assessment/methods , Risk Factors , SARS-CoV-2/isolation & purification
8.
J Appl Physiol (1985) ; 130(3): 865-876, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1028125

ABSTRACT

COVID-19 infection may lead to acute respiratory distress syndrome (CARDS) where severe gas exchange derangements may be associated, at least in the early stages, only with minor pulmonary infiltrates. This may suggest that the shunt associated to the gasless lung parenchyma is not sufficient to explain CARDS hypoxemia. We designed an algorithm (VentriQlar), based on the same conceptual grounds described by J.B. West in 1969. We set 498 ventilation-perfusion (VA/Q) compartments and, after calculating their blood composition (PO2, PCO2, and pH), we randomly chose 106 combinations of five parameters controlling a bimodal distribution of blood flow. The solutions were accepted if the predicted PaO2 and PaCO2 were within 10% of the patient's values. We assumed that the shunt fraction equaled the fraction of non-aerated lung tissue at the CT quantitative analysis. Five critically-ill patients later deceased were studied. The PaO2/FiO2 was 91.1 ± 18.6 mmHg and PaCO2 69.0 ± 16.1 mmHg. Cardiac output was 9.58 ± 0.99 L/min. The fraction of non-aerated tissue was 0.33 ± 0.06. The model showed that a large fraction of the blood flow was likely distributed in regions with very low VA/Q (Qmean = 0.06 ± 0.02) and a smaller fraction in regions with moderately high VA/Q. Overall LogSD, Q was 1.66 ± 0.14, suggestive of high VA/Q inequality. Our data suggest that shunt alone cannot completely account for the observed hypoxemia and a significant VA/Q inequality must be present in COVID-19. The high cardiac output and the extensive microthrombosis later found in the autopsy further support the hypothesis of a pathological perfusion of non/poorly ventilated lung tissue.NEW & NOTEWORTHY Hypothesizing that the non-aerated lung fraction as evaluated by the quantitative analysis of the lung computed tomography (CT) equals shunt (VA/Q = 0), we used a computational approach to estimate the magnitude of the ventilation-perfusion inequality in severe COVID-19. The results show that a severe hyperperfusion of poorly ventilated lung region is likely the cause of the observed hypoxemia. The extensive microthrombosis or abnormal vasodilation of the pulmonary circulation may represent the pathophysiological mechanism of such VA/Q distribution.


Subject(s)
COVID-19/physiopathology , Ventilation-Perfusion Ratio/physiology , Adult , Aged , COVID-19/metabolism , Cardiac Output/physiology , Female , Hemodynamics/physiology , Humans , Lung/metabolism , Lung/physiopathology , Male , Middle Aged , Oxygen/metabolism , Perfusion/methods , Pulmonary Circulation/physiology , Pulmonary Gas Exchange/physiology , Respiration , Retrospective Studies , SARS-CoV-2/pathogenicity
9.
Glycobiology ; 31(4): 372-377, 2021 05 03.
Article in English | MEDLINE | ID: covidwho-917675

ABSTRACT

A large variation in the severity of disease symptoms is one of the key open questions in coronavirus disease 2019 (COVID-19) pandemics. The fact that only a small subset of people infected with severe acute respiratory syndrome coronavirus 2 develops severe disease suggests that there have to be some predisposing factors, but biomarkers that reliably predict disease severity have not been found so far. Since overactivation of the immune system is implicated in a severe form of COVID-19 and the immunoglobulin G (IgG) glycosylation is known to be involved in the regulation of different immune processes, we evaluated the association of interindividual variation in IgG N-glycome composition with the severity of COVID-19. The analysis of 166 severe and 167 mild cases from hospitals in Spain, Italy and Portugal revealed statistically significant differences in the composition of the IgG N-glycome. The most notable difference was the decrease in bisecting N-acetylglucosamine in severe patients from all three cohorts. IgG galactosylation was also lower in severe cases in all cohorts, but the difference in galactosylation was not statistically significant after correction for multiple testing.


Subject(s)
COVID-19/epidemiology , COVID-19/pathology , Immunoglobulin G/metabolism , SARS-CoV-2/isolation & purification , Severity of Illness Index , Adult , Aged , COVID-19/metabolism , COVID-19/virology , Cohort Studies , Female , Glycosylation , Humans , Italy/epidemiology , Male , Middle Aged , Portugal/epidemiology , Spain/epidemiology
10.
Ann Intensive Care ; 10(1): 133, 2020 Oct 12.
Article in English | MEDLINE | ID: covidwho-846400

ABSTRACT

BACKGROUND: A Covid-19 outbreak developed in Lombardy, Veneto and Emilia-Romagna (Italy) at the end of February 2020. Fear of an imminent saturation of available ICU beds generated the notion that rationing of intensive care resources could have been necessary. RESULTS: In order to evaluate the impact of Covid-19 on the ICU capacity to manage critically ill patients, we performed a retrospective analysis of the first 2 weeks of the outbreak (February 24-March 8). Data were collected from regional registries and from a case report form sent to participating sites. ICU beds increased from 1545 to 1989 (28.7%), and patients receiving respiratory support outside the ICU increased from 4 (0.6%) to 260 (37.0%). Patients receiving respiratory support outside the ICU were significantly older [65 vs. 77 years], had more cerebrovascular (5.8 vs. 13.1%) and renal (5.3 vs. 10.0%) comorbidities and less obesity (31.4 vs. 15.5%) than patients admitted to the ICU. PaO2/FiO2 ratio, respiratory rate and arterial pH were higher [165 vs. 244; 20 vs. 24 breath/min; 7.40 vs. 7.46] and PaCO2 and base excess were lower [34 vs. 42 mmHg; 0.60 vs. 1.30] in patients receiving respiratory support outside the ICU than in patients admitted to the ICU, respectively. CONCLUSIONS: Increase in ICU beds and use of out-of-ICU respiratory support allowed effective management of the first 14 days of the Covid-19 outbreak, avoiding resource rationing.

11.
Immunobiology ; 225(6): 152001, 2020 11.
Article in English | MEDLINE | ID: covidwho-696536

ABSTRACT

In COVID-19, acute respiratory distress syndrome (ARDS) and thrombotic events are frequent, life-threatening complications. Autopsies commonly show arterial thrombosis and severe endothelial damage. Endothelial damage, which can play an early and central pathogenic role in ARDS and thrombosis, activates the lectin pathway of complement. Mannan-binding lectin-associated serine protease-2 (MASP-2), the lectin pathway's effector enzyme, binds the nucleocapsid protein of severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2), resulting in complement activation and lung injury. Narsoplimab, a fully human immunoglobulin gamma 4 (IgG4) monoclonal antibody against MASP-2, inhibits lectin pathway activation and has anticoagulant effects. In this study, the first time a lectin-pathway inhibitor was used to treat COVID-19, six COVID-19 patients with ARDS requiring continuous positive airway pressure (CPAP) or intubation received narsoplimab under compassionate use. At baseline and during treatment, circulating endothelial cell (CEC) counts and serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP) and lactate dehydrogenase (LDH) were assessed. Narsoplimab treatment was associated with rapid and sustained reduction of CEC and concurrent reduction of serum IL-6, IL-8, CRP and LDH. Narsoplimab was well tolerated; no adverse drug reactions were reported. Two control groups were used for retrospective comparison, both showing significantly higher mortality than the narsoplimab-treated group. All narsoplimab-treated patients recovered and survived. Narsoplimab may be an effective treatment for COVID-19 by reducing COVID-19-related endothelial cell damage and the resultant inflammation and thrombotic risk.


Subject(s)
Antibodies, Monoclonal/therapeutic use , COVID-19/immunology , Complement Pathway, Mannose-Binding Lectin/drug effects , Endothelium, Vascular/drug effects , SARS-CoV-2/immunology , Thrombotic Microangiopathies/drug therapy , Antibodies, Monoclonal/immunology , C-Reactive Protein/immunology , C-Reactive Protein/metabolism , COVID-19/complications , COVID-19/virology , Complement Pathway, Mannose-Binding Lectin/immunology , Endothelium, Vascular/immunology , Endothelium, Vascular/pathology , Female , Humans , Immunoglobulin G/immunology , Immunoglobulin G/therapeutic use , Inflammation/complications , Inflammation/immunology , Inflammation/prevention & control , Interleukin-6/blood , Interleukin-6/immunology , Male , Mannose-Binding Protein-Associated Serine Proteases/antagonists & inhibitors , Mannose-Binding Protein-Associated Serine Proteases/immunology , Mannose-Binding Protein-Associated Serine Proteases/metabolism , Middle Aged , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical data , Retrospective Studies , SARS-CoV-2/physiology , Thrombotic Microangiopathies/complications , Thrombotic Microangiopathies/immunology
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