Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 553
Filter
1.
Int J Mol Sci ; 21(14)2020 Jul 08.
Article in English | MEDLINE | ID: covidwho-1934087

ABSTRACT

Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are characterized by an inflammatory response, alveolar edema, and hypoxemia. ARDS occurs most often in the settings of pneumonia, sepsis, aspiration of gastric contents, or severe trauma. The prevalence of ARDS is approximately 10% in patients of intensive care. There is no effective remedy with mortality high at 30-40%. Most functional proteins are dynamic and stringently governed by ubiquitin proteasomal degradation. Protein ubiquitination is reversible, the covalently attached monoubiquitin or polyubiquitin moieties within the targeted protein can be removed by a group of enzymes called deubiquitinating enzymes (DUBs). Deubiquitination plays an important role in the pathobiology of ALI/ARDS as it regulates proteins critical in engagement of the alveolo-capillary barrier and in the inflammatory response. In this review, we provide an overview of how DUBs emerge in pathogen-induced pulmonary inflammation and related aspects in ALI/ARDS. Better understanding of deubiquitination-relatedsignaling may lead to novel therapeutic approaches by targeting specific elements of the deubiquitination pathways.


Subject(s)
Acute Lung Injury/metabolism , Deubiquitinating Enzymes/metabolism , Respiratory Distress Syndrome/metabolism , Animals , Humans , Pneumonia/metabolism , Signal Transduction/physiology , Ubiquitin/metabolism , Ubiquitination/physiology
2.
Acta Clin Belg ; 77(1): 211-218, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1900965

ABSTRACT

Angiotensin-converting enzyme 2 (ACE 2) is the entry receptor for the novel coronavirus SARS-CoV-2, the aetiological agent of COVID-19. At the same time, ACE 2 expression decreases during COVID-19. Two seemingly contradictory relationships between the expression of ACE 2 and COVID-19 have been reported. Increased level of expression of ACE 2 may be a risk factor for the development of COVID-19 infection, while reduced ACE 2 expression during COVID-19 leads to acute respiratory distress syndrome. This article provides a comprehensive overview of available scientific knowledge about the role of ACE 2 in the pathogenesis of COVID-19, which is available up to current day. Also, it discusses unknown factors that we will have to reveal in order to understand the whole role of ACE 2 in the pathogenesis of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , COVID-19/pathology , Humans , Respiratory Distress Syndrome/virology , Risk Factors , SARS-CoV-2
3.
Crit Care Med ; 48(12): e1332-e1336, 2020 12.
Article in English | MEDLINE | ID: covidwho-1895840

ABSTRACT

OBJECTIVES: Clinical observation suggests that early acute respiratory distress syndrome induced by the severe acute respiratory syndrome coronavirus 2 may be "atypical" due to a discrepancy between a relatively unaffected static respiratory system compliance and a significant hypoxemia. This would imply an "atypical" response to the positive end-expiratory pressure. DESIGN: Single-center, unblinded, crossover study. SETTING: ICU of Bari Policlinico Academic Hospital (Italy), dedicated to care patients with confirmed diagnosis of novel coronavirus disease 2019. PATIENTS: Eight patients with early severe acute respiratory syndrome coronavirus 2 acute respiratory distress syndrome and static respiratory compliance higher than or equal to 50 mL/cm H2O. INTERVENTIONS: We compared a "lower" and a "higher" positive end-expiratory pressure approach, respectively, according to the intervention arms of the acute respiratory distress syndrome network and the positive end-expiratory pressure setting in adults with acute respiratory distress syndrome studies. MEASUREMENTS AND MAIN RESULTS: Patients were ventilated with the acute respiratory distress syndrome network and, subsequently, with the ExPress protocol. After 1 hour of ventilation, for each protocol, we recorded arterial blood gas, respiratory mechanics, alveolar recruitment, and hemodynamic variables. Comparisons were performed with analysis of variance for repeated measures or Friedman test as appropriate. Positive end-expiratory pressure was increased from 9 ± 3.5 to 17.7 ± 1.7 cm H2O (p < 0.01). Alveolar recruitment was 450 ± 111 mL. Static respiratory system compliance decreased from 58.3 ± 7.6 mL/cm H2O to 47.4 ± 14.5 mL/cm H2O (p = 0.018) and the "stress index" increased from 0.97 ± 0.03 to 1.22 ± 0.07 (p < 0.001). The PaO2/FIO2 ratio increased from 131 ± 22 to 207 ± 41 (p < 0.001), and the PaCO2 increased from 45.9 ± 12.7 to 49.8 ± 13.2 mm Hg (p < 0.001). The cardiac index went from 3.6 ± 0.4 to 2.9 ± 0.6 L/min/m (p = 0.01). CONCLUSIONS: Our data suggest that the "higher" positive end-expiratory pressure approach in patients with severe acute respiratory syndrome coronavirus 2 acute respiratory distress syndrome and high compliance improves oxygenation and lung aeration but may result in alveolar hyperinflation and hemodynamic alterations.


Subject(s)
COVID-19/complications , Positive-Pressure Respiration/methods , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/therapy , Adult , Aged , Aged, 80 and over , Blood Gas Analysis , Cross-Over Studies , Female , Humans , Male , Middle Aged , Respiratory Mechanics/physiology , SARS-CoV-2
4.
Minerva Med ; 113(2): 281-290, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1847990

ABSTRACT

BACKGROUND: The efficacy and safety of continuous positive airway pressure and respiratory physiotherapy outside the Intensive Care Unit during a pandemic. METHODS: In this cohort study performed in February-May 2020 in a large teaching hospital in Milan, COVID-19 patients with adult respiratory distress syndrome receiving continuous positive airway pressure (positive end-expiratory pressure =10 cm H2O, FiO2=0.6, daily treatment duration: 4×3h-cycles) and respiratory physiotherapy including pronation outside the Intensive Care Unit were followed-up. RESULTS: Of 90 acute respiratory distress syndrome (ARDS) patients treated with continuous positive airway pressure (45/90, 50% pronated at least once) outside the Intensive Care Unit and with a median (interquartile) follow-up of 37 (11-46) days, 45 (50%) were discharged at home, 28 (31%) were still hospitalized, and 17 (19%) died. Continuous positive airway pressure failure was recorded for 35 (39%) patients. Patient mobilization was associated with reduced failure rates (P=0.033). No safety issues were observed. CONCLUSIONS: Continuous positive airway pressure with patient mobilization (including pronation) was effective and safe in patients with ARDS due to COVID-19 managed outside the Intensive Care Unit setting during the pandemic.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Adult , COVID-19/complications , COVID-19/therapy , Cohort Studies , Continuous Positive Airway Pressure , Humans , Intensive Care Units , Pronation , Respiratory Distress Syndrome/therapy
5.
Crit Care Explor ; 2(9): e0202, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-1795075

ABSTRACT

OBJECTIVES: Patients with coronavirus disease 2019 acute respiratory distress syndrome appear to present with at least two distinct phenotypes: severe hypoxemia with relatively well-preserved lung compliance and lung gas volumes (type 1) and a more conventional acute respiratory distress syndrome phenotype, displaying the typical characteristics of the "baby lung" (type 2). We aimed to test plausible hypotheses regarding the pathophysiologic mechanisms underlying coronavirus disease 2019 acute respiratory distress syndrome and to evaluate the resulting implications for ventilatory management. DESIGN: We adapted a high-fidelity computational simulator, previously validated in several studies of acute respiratory distress syndrome, to: 1) develop quantitative insights into the key pathophysiologic differences between the coronavirus disease 2019 acute respiratory distress syndrome and the conventional acute respiratory distress syndrome and 2) assess the impact of different positive end-expiratory pressure, Fio2, and tidal volume settings. SETTING: Interdisciplinary Collaboration in Systems Medicine Research Network. SUBJECTS: The simulator was calibrated to represent coronavirus disease 2019 acute respiratory distress syndrome patients with both normal and elevated body mass indices undergoing invasive mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: An acute respiratory distress syndrome model implementing disruption of hypoxic pulmonary vasoconstriction and vasodilation leading to hyperperfusion of collapsed lung regions failed to replicate clinical data on type 1 coronavirus disease 2019 acute respiratory distress syndrome patients. Adding mechanisms to reflect disruption of alveolar gas-exchange due to the effects of pneumonitis and heightened vascular resistance due to the emergence of microthrombi produced levels of ventilation perfusion mismatch and hypoxemia consistent with data from type 1 coronavirus disease 2019 acute respiratory distress syndrome patients, while preserving close-to-normal lung compliance and gas volumes. Atypical responses to positive end-expiratory pressure increments between 5 and 15 cm H2O were observed for this type 1 coronavirus disease 2019 acute respiratory distress syndrome model across a range of measures: increasing positive end-expiratory pressure resulted in reduced lung compliance and no improvement in oxygenation, whereas mechanical power, driving pressure, and plateau pressure all increased. Fio2 settings based on acute respiratory distress syndrome network protocols at different positive end-expiratory pressure levels were insufficient to achieve adequate oxygenation. Incrementing tidal volumes from 5 to 10 mL/kg produced similar increases in multiple indicators of ventilator-induced lung injury in the type 1 coronavirus disease 2019 acute respiratory distress syndrome model to those seen in a conventional acute respiratory distress syndrome model. CONCLUSIONS: Our model suggests that use of standard positive end-expiratory pressure/Fio2 tables, higher positive end-expiratory pressure strategies, and higher tidal volumes may all be potentially deleterious in type 1 coronavirus disease 2019 acute respiratory distress syndrome patients, and that a highly personalized approach to treatment is advisable.

6.
Crit Care Explor ; 2(9): e0207, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-1795073

ABSTRACT

OBJECTIVES: To determine whether placental cell therapy PLacental eXpanded (PLX)-PAD (Pluristem Therapeutics, Haifa, Israel) may be beneficial to treating critically ill patients suffering from acute respiratory distress syndrome due to coronavirus disease 2019. DESIGN: Retrospective case report of critically ill coronavirus disease 2019 patients treated with PLacental eXpanded (PLX)-PAD from March 26, 2020, to April 4, 2020, with follow-up through May 2, 2020. SETTING: Four hospitals in Israel (Rambam Health Care Campus, Bnai Zion Medical Center, and Samson Assuta Ashdod University Hospital), and Holy Name Medical Center in New Jersey. PATIENTS: Eight critically ill patients on invasive mechanical ventilation, suffering from acute respiratory distress syndrome due to coronavirus disease 2019. INTERVENTIONS: Intramuscular injection of PLacental eXpanded (PLX)-PAD (300 × 106 cells) given as one to two treatments. MEASUREMENTS AND MAIN RESULTS: Mortality, time to discharge, and changes in blood and respiratory variables were monitored during hospitalization to day 17 posttreatment. Of the eight patients treated (median age 55 yr, seven males and one female), five were discharged, two remained hospitalized, and one died. By day 3 postinjection, mean C-reactive protein fell 45% (240.3-131.3 mg/L; p = 0.0019) and fell to 77% by day 5 (56.0 mg/L; p < 0.0001). Pao2/Fio2 improved in 5:8 patients after 24-hour posttreatment, with similar effects 48-hour posttreatment. A decrease in positive end-expiratory pressure and increase in pH were statistically significant between days 0 and 14 (p = 0.0032 and p = 0.00072, respectively). A decrease in hemoglobin was statistically significant for days 0-5 and 0-14 (p = 0.015 and p = 0.0028, respectively), whereas for creatinine, it was statistically significant between days 0 and 14 (p = 0.032). CONCLUSIONS: Improvement in several variables such as C-reactive protein, positive end-expiratory pressure, and Pao2/Fio2 was observed following PLacental eXpanded (PLX)-PAD treatment, suggesting possible therapeutic effect. However, interpretation of the data is limited due to the small sample size, use of concomitant investigational therapies, and the uncontrolled study design. The efficacy of PLacental eXpanded (PLX)-PAD in coronavirus disease 2019 should be further evaluated in a controlled clinical trial.

7.
Trials ; 22(1): 172, 2021 Mar 01.
Article in English | MEDLINE | ID: covidwho-1622253

ABSTRACT

OBJECTIVES: The primary objective of this study is to test the hypothesis that administration of dexamethasone 20 mg is superior to a 6 mg dose in adult patients with moderate or severe ARDS due to confirmed COVID-19. The secondary objective is to investigate the efficacy and safety of dexamethasone 20 mg versus dexamethasone 6 mg. The exploratory objective of this study is to assess long-term consequences on mortality and quality of life at 180 and 360 days. TRIAL DESIGN: REMED is a prospective, phase II, open-label, randomised controlled trial testing superiority of dexamethasone 20 mg vs 6 mg. The trial aims to be pragmatic, i.e. designed to evaluate the effectiveness of the intervention in conditions that are close to real-life routine clinical practice. PARTICIPANTS: The study is multi-centre and will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic. INCLUSION CRITERIA: Subjects will be eligible for the trial if they meet all of the following criteria: 1. Adult (≥18 years of age) at time of enrolment; 2. Present COVID-19 (infection confirmed by RT-PCR or antigen testing); 3. Intubation/mechanical ventilation or ongoing high-flow nasal cannula (HFNC) oxygen therapy; 4. Moderate or severe ARDS according to Berlin criteria: • Moderate - PaO2/FiO2 100-200 mmHg; • Severe - PaO2/FiO2 < 100 mmHg; 5. Admission to ICU in the last 24 hours. EXCLUSION CRITERIA: Subjects will not be eligible for the trial if they meet any of the following criteria: 1. Known allergy/hypersensitivity to dexamethasone or excipients of the investigational medicinal product (e.g. parabens, benzyl alcohol); 2. Fulfilled criteria for ARDS for ≥14 days at enrolment; 3. Pregnancy or breastfeeding; 4. Unwillingness to comply with contraception measurements from enrolment until at least 1 week after the last dose of dexamethasone (sexual abstinence is considered an adequate contraception method); 5. End-of-life decision or patient is expected to die within next 24 hours; 6. Decision not to intubate or ceilings of care in place; 7. Immunosuppression and/or immunosuppressive drugs in medical history: a) Systemic immunosuppressive drugs or chemotherapy in the past 30 days; b) Systemic corticosteroid use before hospitalization; c) Any dose of dexamethasone during the present hospital stay for COVID-19 for ≥5 days before enrolment; d) Systemic corticosteroids during present hospital stay for conditions other than COVID-19 (e.g. septic shock); 8. Current haematological or generalized solid malignancy; 9. Any contraindication for corticosteroid administration, e.g. • intractable hyperglycaemia; • active gastrointestinal bleeding; • adrenal gland disorders; • presence of superinfection diagnosed with locally established clinical and laboratory criteria without adequate antimicrobial treatment; 10. Cardiac arrest before ICU admission; 11. Participation in another interventional trial in the last 30 days. INTERVENTION AND COMPARATOR: Dexamethasone solution for injection/infusion is the investigational medicinal product as well as the comparator. The trial will assess two doses, 20 mg (investigational) vs 6 mg (comparator). Patients in the intervention group will receive dexamethasone 20 mg intravenously once daily on day 1-5, followed by dexamethasone 10 mg intravenously once daily on day 6-10. Patients in the control group will receive dexamethasone 6 mg day 1-10. All authorized medicinal products containing dexamethasone in the form of solution for i.v. injection/infusion can be used. MAIN OUTCOMES: Primary endpoint: Number of ventilator-free days (VFDs) at 28 days after randomisation, defined as being alive and free from mechanical ventilation. SECONDARY ENDPOINTS: a) Mortality from any cause at 60 days after randomisation; b) Dynamics of inflammatory marker (C-Reactive Protein, CRP) change from Day 1 to Day 14; c) WHO Clinical Progression Scale at Day 14; d) Adverse events related to corticosteroids (new infections, new thrombotic complications) until Day 28 or hospital discharge; e) Independence at 90 days after randomisation assessed by Barthel Index. The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days through telephone structured interviews using the Barthel Index. RANDOMISATION: Randomisation will be carried out within the electronic case report form (eCRF) by the stratified permuted block randomisation method. Allocation sequences will be prepared by a statistician independent of the study team. Allocation to the treatment arm of an individual patient will not be available to the investigators before completion of the whole randomisation process. The following stratification factors will be applied: • Age <65 and ≥ 65; • Charlson Comorbidity index (CCI) <3 and ≥3; • CRP <150 mg/L and ≥150 mg/L • Trial centre. Patients will be randomised in a 1 : 1 ratio into one of the two treatment arms. Randomisation through the eCRF will be available 24 hours every day. BLINDING (MASKING): This is an open-label trial in which the participants and the study staff will be aware of the allocated intervention. Blinded pre-planned statistical analysis will be performed. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size is calculated to detect the difference of 3 VFDs at 28 days (primary efficacy endpoint) between the two treatment arms with a two-sided type I error of 0.05 and power of 80%. Based on data from a multi-centre randomised controlled trial in COVID-19 ARDS patients in Brazil and a multi-centre observational study from French and Belgian ICUs regarding moderate to severe ARDS related to COVID-19, investigators assumed a standard deviation of VFD at 28 days as 9. Using these assumptions, a total of 142 patients per treatment arm would be needed. After adjustment for a drop-out rate, 150 per treatment arm (300 patients per study) will be enrolled. TRIAL STATUS: This is protocol version 1.1, 15.01.2021. The trial is due to start on 2 February 2021 and recruitment is expected to be completed by December 2021. TRIAL REGISTRATION: The study protocol was registered on EudraCT No.:2020-005887-70, and on December 11, 2020 on ClinicalTrials.gov (Title: Effect of Two Different Doses of Dexamethasone in Patients With ARDS and COVID-19 (REMED)) Identifier: NCT04663555 with a last update posted on February 1, 2021. FULL PROTOCOL: The full protocol (version 1.1) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the standard formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
COVID-19/therapy , Dexamethasone/administration & dosage , Glucocorticoids/administration & dosage , Respiration, Artificial , Respiratory Distress Syndrome/therapy , COVID-19/complications , Clinical Trials, Phase II as Topic , Disease Progression , Dose-Response Relationship, Drug , Equivalence Trials as Topic , Humans , Length of Stay , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Respiratory Distress Syndrome/etiology , SARS-CoV-2
8.
Ann Med ; 53(1): 410-412, 2021 12.
Article in English | MEDLINE | ID: covidwho-1573909

ABSTRACT

OBJECTIVE: Cytokine release syndrome is suggested to be the most important mechanism triggering acute respiratory distress syndrome and end organ damage in COVID-19. The severity of disease may be measured by different biomarkers. METHODS: We studied markers of inflammation and coagulation as recorded in 29 patients on admission to the hospital in order to identify markers of severe COVID-19 and need of ICU. RESULTS: Patients who were eventually admitted to ICU displayed significantly higher serum levels of interleukin-6 (IL-6), C-reactive protein (CRP), and procalcitonin. No statistical differences were found between the groups in median levels of lymphocytes, D-dimer or ferritin. CONCLUSIONS: IL-6 and CRP were the strongest predictors of severity in hospitalized patients with COVID-19.


Subject(s)
COVID-19/blood , COVID-19/diagnosis , Interleukin-6/blood , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Female , Humans , Male , Middle Aged , Severity of Illness Index , Young Adult
9.
Clin Infect Dis ; 73(11): e4005-e4011, 2021 12 06.
Article in English | MEDLINE | ID: covidwho-1562130

ABSTRACT

BACKGROUND: Racial disparities are central in the national conversation about coronavirus disease 2019 (COVID-19) , with Black/African Americans being disproportionately affected. We assessed risk factors for death from COVID-19 among Black inpatients at an urban hospital in Detroit, Michigan. METHODS: This was a retrospective, single-center cohort study. We reviewed the electronic medical records of patients positive for severe acute respiratory syndrome coronavirus 2 (the COVID-19 virus) on qualitative polymerase chain reaction assay who were admitted between 8 March 2020 and 6 May 2020. The primary outcome was in-hospital mortality. RESULTS: The case fatality rate was 29.1% (122/419). The mean duration of symptoms prior to hospitalization was 5.3 (3.9) days. The incidence of altered mental status on presentation was higher among patients who died than those who survived, 43% vs 20.0%, respectively (P < .0001). From multivariable analysis, the odds of death increased with age (≥60 years), admission from a nursing facility, Charlson score, altered mental status, higher C-reactive protein on admission, need for mechanical ventilation, presence of shock, and acute respiratory distress syndrome. CONCLUSIONS: These demographic, clinical, and laboratory factors may help healthcare providers identify Black patients at highest risk for severe COVID-19-associated outcomes. Early and aggressive interventions among this at-risk population may help mitigate adverse outcomes.


Subject(s)
COVID-19 , African Americans , Cohort Studies , Hospital Mortality , Hospitalization , Humans , Middle Aged , Retrospective Studies , Risk Factors , SARS-CoV-2
10.
Curr Opin Organ Transplant ; 26(3): 302-308, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1526214

ABSTRACT

PURPOSE OF REVIEW: Over the past two decades, lung transplant has become the mainstay of treatment for several end-stage lung diseases. As the field continues to evolve, the criteria for referral and listing have also changed. The last update to these guidelines was in 2014 and several studies since then have changed how patients are transplanted. Our article aims to briefly discuss these updates in lung transplantation. RECENT FINDINGS: This article discusses the importance of early referral of patients for lung transplantation and the concept of the 'transplant window'. We review the referral and listing criteria for some common pulmonary diseases and also cite the updated literature surrounding the absolute and relative contraindications keeping in mind that they are a constantly moving target. Frailty and psychosocial barriers are difficult to assess with the current assessment tools but continue to impact posttransplant outcomes. Finally, we discuss the limited data on transplantation in acute respiratory distress syndrome (ARDS) due to COVID19 as well as extracorporeal membrane oxygenation bridge to transplantation. SUMMARY: The findings discussed in this article will strongly impact, if not already, how we select candidates for lung transplantation. It also addresses some aspects of lung transplant such as frailty and ARDS, which need better assessment tools and clinical data.


Subject(s)
Lung Diseases , Lung Transplantation , COVID-19 , Humans , Lung Diseases/surgery , Lung Transplantation/adverse effects , Patient Selection , SARS-CoV-2
11.
Surg Infect (Larchmt) ; 22(9): 948-954, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1522102

ABSTRACT

Background: In trauma, direct pulmonary injury and innate immune response activation primes the lungs for acute respiratory distress syndrome (ARDS). The inflammasome-dependent release of interleukin-18 (IL-18) was recently identified as a key mediator in ARDS pathogenesis, leading us to hypothesize that plasma IL-18 is a diagnostic predictor of ARDS in severe blunt trauma. Patients and Methods: Secondary analysis of the Inflammation and Host Response to Injury database was performed on plasma cytokines collected within 12 hours of severe blunt trauma. Trauma-related cytokines, including IL-18, were compared between patients with and without ARDS and were evaluated for association with ARDS using regression analysis. Threshold cytokine concentrations predictive of ARDS were determined using receiver-operating curve (ROC) analysis. Results: Cytokine analysis of patients without ARDS patients (n = 61) compared with patients with ARDS (n = 19) demonstrated elevated plasma IL-18 concentration in ARDS and IL-18 remained correlated with ARDS on logistic regression after confounder adjustment (p = 0.008). Additionally, ROC analysis revealed IL-18 as a strong ARDS predictor (area under the curve [AUC] = 0.83), with a threshold IL-18 value of 170 pg/mL (Youden index, 0.3). Unlike in patients without ARDS, elevated IL-18 persisted in patients with ARDS during the acute injury phase (p ≤ 0.02). Other trauma-related cytokines did not correlate with ARDS. Conclusions: In severe blunt trauma, IL-18 is a robust predictor of ARDS and remains elevated throughout the acute injury phase. These findings support the use of IL-18 as a key ARDS biomarker, promoting early identification of trauma patients at greater risk of developing ARDS. Timely recognition of ARDS and implementation of advantageous supportive care practices may reduce trauma-related ARDS morbidity and costs.


Subject(s)
Respiratory Distress Syndrome , Wounds, Nonpenetrating , Humans , Interleukin-18 , Logistic Models , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/etiology , Risk Assessment , Wounds, Nonpenetrating/complications , Wounds, Nonpenetrating/diagnosis
12.
Intensive Care Med ; 46(12): 2284-2296, 2020 12.
Article in English | MEDLINE | ID: covidwho-1451948

ABSTRACT

Current literature addressing the pharmacological principles guiding glucocorticoid (GC) administration in ARDS is scant. This paucity of information may have led to the heterogeneity of treatment protocols and misinterpretation of available findings. GCs are agonist compounds that bind to the GC receptor (GR) producing a pharmacological response. Clinical efficacy depends on the magnitude and duration of exposure to GR. We updated the meta-analysis of randomized trials investigating GC treatment in ARDS, focusing on treatment protocols and response. We synthesized the current literature on the role of the GR in GC therapy including genomic and non-genomic effects, and integrated current clinical pharmacology knowledge of various GCs, including hydrocortisone, methylprednisolone and dexamethasone. This review addresses the role dosage, timing of initiation, mode of administration, duration, and tapering play in achieving optimal response to GC therapy in ARDS. Based on RCTs' findings, GC plasma concentration-time profiles, and pharmacodynamic studies, optimal results are most likely achievable with early intervention, an initial bolus dose to achieve close to maximal GRα saturation, followed by a continuous infusion to maintain high levels of response throughout the treatment period. In addition, patients receiving similar GC doses may experience substantial between-patient variability in plasma concentrations affecting clinical response. GC should be dose-adjusted and administered for a duration targeting clinical and laboratory improvement, followed by dose-tapering to achieve gradual recovery of the suppressed hypothalamic-pituitary-adrenal (HPA) axis. These findings have practical clinical relevance. Future RCTs should consider these pharmacological principles in the study design and interpretation of findings.


Subject(s)
Glucocorticoids , Respiratory Distress Syndrome , Humans , Hypothalamo-Hypophyseal System , Methylprednisolone , Pituitary-Adrenal System , Respiratory Distress Syndrome/drug therapy
13.
Med Sci Monit ; 26: e922281, 2020 Mar 31.
Article in English | MEDLINE | ID: covidwho-1453382

ABSTRACT

BACKGROUND Acute respiratory distress syndrome (ARDS) is a sudden and serious disease with increasing morbidity and mortality rates. Phosphodiesterase 4 (PDE4) is a novel target for inflammatory disease, and ibudilast (IBU), a PDE4 inhibitor, inhibits inflammatory response. Our study investigated the effect of IBU on the pathogenesis of neonatal ARDS and the underlying mechanism related to it. MATERIAL AND METHODS Western blotting was performed to analyze the expression levels of PDE4, CXCR4, SDF-1, CXCR5, CXCL1, inflammatory cytokines, and proteins related to cell apoptosis. Hematoxylin-eosin staining was performed to observe the pathological morphology of lung tissue. Pulmonary edema score was used to assess the degree of lung water accumulation after pulmonary injury. Enzyme-linked immunosorbent assay (ELISA) was used to assess levels of inflammatory factors (TNF-alpha, IL-1ß, IL-6, and MCP-1) in serum. TUNEL assay was used to detect apoptotic cells. RESULTS Increased expression of PDE4 was observed in an LPS-induced neonatal ARDS mouse model, and IBU ameliorated LPS-induced pathological manifestations and pulmonary edema in lung tissue. In addition, IBU attenuated the secretion of inflammatory cytokines by inactivating the chemokine axis in the LPS-induced neonatal ARDS mouse model. Finally, IBU significantly reduced LPS-induced cell apoptosis in lung tissue. CONCLUSIONS IBU, a PDE4 inhibitor, protected against ARDS by interfering with pulmonary inflammation and apoptosis. Our findings provide a novel and promising strategy to regulate pulmonary inflammation in ARDS.


Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Inflammation/drug therapy , Phosphodiesterase 4 Inhibitors/pharmacology , Pyridines/pharmacology , Respiratory Distress Syndrome, Newborn/drug therapy , Animals , Animals, Newborn , Apoptosis/drug effects , Apoptosis/immunology , Bronchoalveolar Lavage Fluid , Disease Models, Animal , Humans , Inflammation/diagnosis , Inflammation/immunology , Inflammation/pathology , Injections, Intraperitoneal , Lipopolysaccharides/immunology , Lung/drug effects , Lung/immunology , Lung/pathology , Mice , Phosphodiesterase 4 Inhibitors/therapeutic use , Pyridines/therapeutic use , Respiratory Distress Syndrome, Newborn/diagnosis , Respiratory Distress Syndrome, Newborn/immunology , Respiratory Distress Syndrome, Newborn/pathology , Signal Transduction/drug effects , Signal Transduction/immunology
14.
Am J Respir Crit Care Med ; 203(5): 575-584, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1452989

ABSTRACT

Rationale: Obesity is characterized by elevated pleural pressure (Ppl) and worsening atelectasis during mechanical ventilation in patients with acute respiratory distress syndrome (ARDS).Objectives: To determine the effects of a lung recruitment maneuver (LRM) in the presence of elevated Ppl on hemodynamics, left and right ventricular pressure, and pulmonary vascular resistance. We hypothesized that elevated Ppl protects the cardiovascular system against high airway pressure and prevents lung overdistension.Methods: First, an interventional crossover trial in adult subjects with ARDS and a body mass index ≥ 35 kg/m2 (n = 21) was performed to explore the hemodynamic consequences of the LRM. Second, cardiovascular function was studied during low and high positive end-expiratory pressure (PEEP) in a model of swine with ARDS and high Ppl (n = 9) versus healthy swine with normal Ppl (n = 6).Measurements and Main Results: Subjects with ARDS and obesity (body mass index = 57 ± 12 kg/m2) after LRM required an increase in PEEP of 8 (95% confidence interval [95% CI], 7-10) cm H2O above traditional ARDS Network settings to improve lung function, oxygenation and [Formula: see text]/[Formula: see text] matching, without impairment of hemodynamics or right heart function. ARDS swine with high Ppl demonstrated unchanged transmural left ventricular pressure and systemic blood pressure after the LRM protocol. Pulmonary arterial hypertension decreased (8 [95% CI, 13-4] mm Hg), as did vascular resistance (1.5 [95% CI, 2.2-0.9] Wood units) and transmural right ventricular pressure (10 [95% CI, 15-6] mm Hg) during exhalation. LRM and PEEP decreased pulmonary vascular resistance and normalized the [Formula: see text]/[Formula: see text] ratio.Conclusions: High airway pressure is required to recruit lung atelectasis in patients with ARDS and class III obesity but causes minimal overdistension. In addition, patients with ARDS and class III obesity hemodynamically tolerate LRM with high airway pressure.Clinical trial registered with www.clinicaltrials.gov (NCT02503241).


Subject(s)
Pulmonary Atelectasis , Respiratory Distress Syndrome , Shock , Animals , Hemodynamics/physiology , Humans , Obesity/complications , Positive-Pressure Respiration/methods , Respiratory Distress Syndrome/therapy , Swine
15.
Phytother Res ; 35(9): 4988-5006, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1432473

ABSTRACT

The SARS-CoV-2 virus, responsible for COVID-19, spread rapidly worldwide and became a pandemic in 2020. In some patients, the virus remains in the respiratory tract, causing pneumonia, respiratory failure, acute respiratory distress syndrome (ARDS), and sepsis, leading to death. Natural flavonoids (aglycone and glycosides) possess broad biological activities encompassing antiinflammatory, antiviral, antitumoral, antiallergic, antiplatelet, and antioxidant effects. While many studies have focused on the effects of natural flavonoids in experimental models, reports based on clinical trials are still insufficient. In this review, we highlight the effects of flavonoids in controlling pulmonary diseases, particularly the acute respiratory distress syndrome, a consequence of COVID-19, and their potential use in coronavirus-related diseases. Furthermore, we also focus on establishing a relationship between biological potential and chemical aspects of related flavonoids and discuss several possible mechanisms of action, pointing out some possible effects on COVID-19.


Subject(s)
COVID-19 , Flavonoids , Lung Injury , COVID-19/complications , Flavonoids/pharmacology , Humans , Lung Injury/drug therapy , Lung Injury/virology , Pandemics
16.
Curr Cardiol Rev ; 17(4): e230421189016, 2021.
Article in English | MEDLINE | ID: covidwho-1435702

ABSTRACT

In December 2019, a novel COVID-19 infection caused by SARS-CoV-2 has emerged as a global emergency. In a few months, the pathogen has infected millions of people in the world. Primarily SARS-CoV-2 infects the pulmonary system which ultimately leads to ARDS and lung failure. The majority of patients develop milder symptoms but the infection turns severe in a huge number of people, which ultimately results in enhanced mortality in COVID-19 patients. Co-morbid conditions, primarily cardiovascular complications and diabetes, have been reported to show a strong correlation with COVID-19 severity. Further, the onset of myocardial injury secondary to pulmonary damage has been observed in critically ill patients who have never reported heart-related ailments before. Due to drastic health risks associated with virus infection, the unprecedented disruption in normal business throughout the world has caused economic misery. Apparently, newer treatments are urgently needed to combat the virus particularly to reduce the severity burden. Therefore, understanding the crosstalk between lung and heart during COVID-19 might give us better clarity for early diagnosis followed by appropriate treatment in patients with the likelihood of developing severe symptoms. Accordingly, the present review highlights the potential mechanisms that may explain the crosstalk between lung and heart so that effective treatment/management strategies can be evolved swiftly in this direction.


Subject(s)
COVID-19 , Heart Diseases , Heart , Heart Diseases/virology , Humans , Lung/pathology , Lung/virology , SARS-CoV-2
18.
Trials ; 22(1): 288, 2021 Apr 19.
Article in English | MEDLINE | ID: covidwho-1388815

ABSTRACT

OBJECTIVES: The primary objective is to demonstrate that, in patients with PCR-confirmed SARS-CoV-2 resulting in Acute Respiratory Distress Syndrome (ARDS), administration of 120mg/kg of body weight of intravenous Prolastin®(plasma-purified alpha-1 antitrypsin) reduces circulating plasma levels of interleukin-6 (IL-6). Secondary objectives are to determine the effects of intravenous Prolastin® on important clinical outcomes including the incidence of adverse events (AEs) and serious adverse events (SAEs). TRIAL DESIGN: Phase 2, randomised, double-blind, placebo-controlled, pilot trial. PARTICIPANTS: The study will be conducted in Intensive Care Units in hospitals across Ireland. Patients with a laboratory-confirmed diagnosis of SARS-CoV-2-infection, moderate to severe ARDS (meeting Berlin criteria for a diagnosis of ARDS with a PaO2/FiO2 ratio <200 mmHg), >18 years of age and requiring invasive or non-invasive mechanical ventilation. All individuals meeting any of the following exclusion criteria at baseline or during screening will be excluded from study participation: more than 96 hours has elapsed from onset of ARDS; age < 18 years; known to be pregnant or breastfeeding; participation in a clinical trial of an investigational medicinal product (other than antibiotics or antivirals) within 30 days; major trauma in the prior 5 days; presence of any active malignancy (other than nonmelanoma skin cancer) which required treatment within the last year; WHO Class III or IV pulmonary hypertension; pulmonary embolism prior to hospital admission within past 3 months; currently receiving extracorporeal life support (ECLS); chronic kidney disease receiving dialysis; severe chronic liver disease with Child-Pugh score > 12; DNAR (Do Not Attempt Resuscitation) order in place; treatment withdrawal imminent within 24 hours; Prisoners; non-English speaking patients or those who do not adequately understand verbal or written information unless an interpreter is available; IgA deficiency. INTERVENTION AND COMPARATOR: Intervention: Either a once weekly intravenous infusion of Prolastin® at 120mg/kg of body weight for 4 weeks or a single dose of Prolastin® at 120mg/kg of body weight intravenously followed by once weekly intravenous infusion of an equal volume of 0.9% sodium chloride for a further 3 weeks. Comparator (placebo): An equal volume of 0.9% sodium chloride intravenously once per week for four weeks. MAIN OUTCOMES: The primary effectiveness outcome measure is the change in plasma concentration of IL-6 at 7 days as measured by ELISA. Secondary outcomes include: safety and tolerability of Prolastin® in the respective groups (as defined by the number of SAEs and AEs); PaO2/FiO2 ratio; respiratory compliance; sequential organ failure assessment (SOFA) score; mortality; time on ventilator in days; plasma concentration of alpha-1 antitrypsin (AAT) as measured by nephelometry; plasma concentrations of interleukin-1ß (IL-1ß), interleukin-8 (IL-8), interleukin-10 (IL-10), soluble TNF receptor 1 (sTNFR1, a surrogate marker for TNF-α) as measured by ELISA; development of shock; acute kidney injury; need for renal replacement therapy; clinical relapse, as defined by the need for readmission to the ICU or a marked decline in PaO2/FiO2 or development of shock or mortality following a period of sustained clinical improvement; secondary bacterial pneumonia as defined by the combination of radiographic findings and sputum/airway secretion microscopy and culture. RANDOMISATION: Following informed consent/assent patients will be randomised. The randomisation lists will be prepared by the study statistician and given to the unblinded trial personnel. However, the statistician will not be exposed to how the planned treatment will be allocated to the treatment codes. Randomisation will be conducted in a 1:1:1 ratio, stratified by site and age. BLINDING (MASKING): The investigator, treating physician, other members of the site research team and patients will be blinded to treatment allocation. The clinical trial pharmacy personnel and research nurses will be unblinded to facilitate intervention and placebo preparation. The unblinded individuals will keep the treatment information confidential. The infusion bag will be masked at the time of preparation and will be administered via a masked infusion set to maintain blinding. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 36 patients will be recruited and randomised in a 1:1:1 ratio to each of the trial arms. TRIAL STATUS: In March 2020, version 1.0 of the trial protocol was submitted to the local research ethics committee (REC), Health Research Consent Declaration Committee (HRCDC) and the Health Products regulatory Authority (HPRA). REC approval was granted on April 1st 2020, HPRA approval was granted on April 24th 2020 and the HRCDC provided a conditional declaration on April 17th 2020. In July 2020 a substantial amendment (version 2.0) was submitted to the REC, HRCDC and HPRA. Protocol changes in this amendment included: the addition of trial sites; extending the duration of the trial to 12 months from 3 months; removal of inclusion criteria requiring the need for vasopressors; amendment of randomisation schedule to stratify by age only and not BMI and sex; correction of grammatical error in relation to infusion duration; to allow for inclusion of subjects who may have been enrolled in a clinical trial involving either antibiotics or anti-virals in the past 30 days; to allow for inclusion of subjects who may be currently enrolled in a clinical trial involving either antibiotics or anti-virals; to remove the need for exclusion based on alpha-1 antitrypsin phenotype; removal of mandatory isoelectric focusing of plasma to confirm Pi*MM status at screening; removal of need for mandatory echocardiogram at screening; amendment on procedures around plasma analysis to reflect that this will be conducted at the central site laboratory (as trial is multi-site and no longer single site); wording amended to reflect that interim analysis of cytokine levels taken at 7 days may be conducted. HRCDC approved version 2.0 on September 14th 2020, and HPRA approved on October 22nd 2020. REC approved the substantial amendment on November 23rd. In November 2020, version 3.0 of the trial protocol was submitted to the REC and HPRA. The rationale for this amendment was to allow for patients with moderate to severe ARDS from SARS-CoV-2 with non-invasive ventilation. HPRA approved this amendment on December 1st 2020 and the REC approved the amendment on December 8th 2020. Patient recruitment commenced in April 2020 and the last patient will be recruited to the trial in April 2021. The last visit of the last patient is anticipated to occur in April 2021. At time of writing, patient recruitment is now complete, however follow-up patient visits and data collection are ongoing. TRIAL REGISTRATION: EudraCT 2020-001391-15 (Registered 31 Mar 2020). FULL PROTOCOL: The full protocol (version 3.0 23.11.2020) is attached as an additional file accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Subject(s)
COVID-19/drug therapy , Respiratory Distress Syndrome/drug therapy , alpha 1-Antitrypsin/therapeutic use , Double-Blind Method , Humans , Ireland , Pilot Projects , Plasma , Randomized Controlled Trials as Topic , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/diagnosis , alpha 1-Antitrypsin/administration & dosage
19.
Cell Res ; 31(8): 847-860, 2021 08.
Article in English | MEDLINE | ID: covidwho-1387284

ABSTRACT

Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.


Subject(s)
Antiviral Agents/metabolism , COVID-19/pathology , Coronavirus Envelope Proteins/metabolism , Respiratory Distress Syndrome/etiology , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Apoptosis , COVID-19/complications , COVID-19/drug therapy , COVID-19/virology , Coronavirus Envelope Proteins/antagonists & inhibitors , Coronavirus Envelope Proteins/genetics , Cytokines/metabolism , Disease Models, Animal , Half-Life , Humans , Lung/metabolism , Lung/pathology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutagenesis, Site-Directed , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity , Spleen/metabolism , Spleen/pathology , Viral Load , Virulence
20.
Med Hypotheses ; 144: 109976, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-1386300

ABSTRACT

Several attempts to control the dreadfulness of SARS-CoV-2 are still underway. Based on the literature evidences we have speculated a prospective contemporary remedy, which was categorized into Specificity, Remedy, and a Conveyor. In which, pros and cons were discussed and inferred the possible alternatives. (a) Specificity: Implicit to express the ACE2 receptors in conveyor cells to deceive SARS-CoV-2 frompreponetargets. (b) Remedy: As depletion of pulmonary surfactants causes strong acute respiratory distress syndrome, we propose an entity of a cost-effective artificialsurfactantsystem as a remedy to pulmonary complications. (c) Conveyor: We propose red blood cells (RBCs) as a conveyor with embedded artificial surfactant and protruding ACE2 receptors for the target-specific delivery. Overall we postulate focused insights by employing a combinational contemporary strategy to steer towards a prospective direction on combating SARS-CoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2/therapeutic use , COVID-19/virology , Erythrocytes , Pulmonary Surfactants/therapeutic use , Receptors, Virus/therapeutic use , SARS-CoV-2/physiology , Viral Tropism , Angiotensin-Converting Enzyme 2/administration & dosage , COVID-19/complications , COVID-19/prevention & control , Drug Costs , Drug Delivery Systems , Humans , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/virology , Pulmonary Surfactants/administration & dosage , Pulmonary Surfactants/chemical synthesis , Pulmonary Surfactants/economics , Receptors, Virus/administration & dosage , Respiratory Distress Syndrome/prevention & control
SELECTION OF CITATIONS
SEARCH DETAIL